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1.
J Photochem Photobiol B ; 200: 111635, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31671372

RESUMO

Parkinson disease is one of the most common neurological movement disorders affecting geriatric population. Biosynthesized gold nanoparticles are the ideal alternatives spotlighted by many researchers to treat various diseases. In the present study we synthesized gold nanoparticles using the root extract of Paeonia mountan, woody trees which are used in traditional Chinese medicine to be prescribed for diverse diseases. The synthesis of gold nanoparticles was confirmed with UV-Vis spectroscopic analysis and characterized using FTIR, HR-TEM, EDAX and XRD analysis. The cytotoxicity property of synthesized gold nanoparticles was assessed using MTT assay in the murine microglial BV2 cells. The neuroprotective effect of synthesized gold nanoparticles in inflammatory agent lipopolysaccharides triggered murine microglial BV2 cells was evaluated using nitric oxide, prostaglandin E2 and inflammatory cytokines assays such as IL-6&IL-1ß. Further to confirm in vivo effect of synthesized nanoparticles, the nanoparticles were treated to Parkinson induced C57BL/6 mice. Behavioral, biochemical and molecular analysis were performed to estimate the potency of synthesized gold nanoparticles against the Parkinson induction in mice model. Our characterization results prove the gold nanoparticles synthesized using Paeonia mountan fulfills the requirement of ideal nanodrug and it potentially inhibited the inflammation in in vitro murine microglial BV2. The results of in vivo experiments authentically confirm gold nanoparticles synthesized using Paeonia mountan alleviates the neuroinflammation and improves the motor coordination in Parkinson induced mice.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Fármacos Neuroprotetores/química , Paeonia/química , Extratos Vegetais/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Química Verde , Lipopolissacarídeos/farmacologia , Masculino , Nanopartículas Metálicas/uso terapêutico , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico/metabolismo , Paeonia/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Doença de Parkinson/veterinária , Raízes de Plantas/química , Raízes de Plantas/metabolismo
2.
Sheng Li Xue Bao ; 71(5): 732-740, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646327

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by loss of dopaminergic (DA) neurons in the dense part of the substantia nigra (SNpc). Postmortem analysis of PD patients and experimental animal studies found that microglial cell activation and increased levels of pro-inflammatory factors were common features of PD brain tissue. At the same time, the invasion and accumulation of peripheric immune cells were detected in the brain of PD patients. In this paper, peripheral inflammation across the blood-brain barrier (BBB), the misfolded α-synuclein (α-syn)-induced microglial cell activation and intracerebral inflammation in PD are summarized, providing potential therapeutic measures for delaying the onset of PD.


Assuntos
Inflamação/patologia , Doença de Parkinson/patologia , Substância Negra/patologia , Animais , Barreira Hematoencefálica , Neurônios Dopaminérgicos/patologia , Humanos , Microglia , alfa-Sinucleína
3.
BMC Neurol ; 19(1): 260, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660902

RESUMO

BACKGROUND: Parkinsonism is a complex multifactorial neurodegenerative disorder, in which genetic and environmental risk factors may both play a role. Among environmental risk factors cocaine was earlier ambiguously linked to Parkinsonism. Former single case reports described Parkinsonism in chronic cocaine users, but an epidemiological study did not confirm an increased risk of Parkinson's disease. Here we report a patient, who developed Parkinsonism in young age after chronic cocaine use, in whom a homozygous LRRK2 risk variant was also detected. CASE PRESENTATION: The patient was investigated because of hand tremor, which started after a 1.5-year period of cocaine abuse. Neurological examination suggested Parkinsonism, and asymmetrical pathology was confirmed by the dopamine transporter imaging study. The genetic investigations revealed a homozygous risk allele in the LRRK2 gene. After a period of cocaine abstinence, the patient's symptoms spontaneously regressed, and the dopamine transporter imaging also returned to near-normal. CONCLUSIONS: This case report suggests that cocaine abuse indeed might be linked to secondary Parkinsonism and serves as an example of a potential gene-environmental interaction between the detected LRRK2 risk variant and cocaine abuse. The reversible nature of the DaTscan pathology is a unique feature of this case, and needs further evaluation, whether this is incidental or can be a feature of cocaine related Parkinsonism.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/complicações , Interação Gene-Ambiente , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/etiologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Masculino , Neuroimagem/métodos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Fatores de Risco , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
4.
Int J Mol Sci ; 20(18)2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505809

RESUMO

Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer's disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson's disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid ß 42 (Aß42) degradation product Aß38, and this indicator of Aß42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aß42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aß deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Lisossomos/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Lisossomos/genética , Lisossomos/patologia , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Sinapses/metabolismo , Sinapses/patologia
5.
Oxid Med Cell Longev ; 2019: 4578462, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485291

RESUMO

Parkinson's disease (PD), clinically characterized by motor and nonmotor symptoms, is a common progressive and multisystem neurodegenerative disorder, which is caused by both genetic and environmental risk factors. The main pathological features of PD are the loss of dopaminergic (DA) neurons and the accumulation of alpha-synuclein (α-syn) in the residual DA neurons in the substantia nigra pars compacta (SNpc). In recent years, substantial progress has been made in discovering the genetic factors of PD. In particular, a total of 19 PD-causing genes have been unraveled, among which some members have been regarded to be related to mitochondrial dysfunction. Mitochondria are key regulators of cellular metabolic activity and are critical for many important cellular processes including energy metabolism and even cell death. Their normal function is basically maintained by the mitochondrial quality control (MQC) mechanism. Accordingly, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a kind of neurotoxin, exerts its neurotoxic effects at least partially by producing its toxic metabolite, namely, 1-methyl-4-phenylpyridine (MPP+), which in turn causes mitochondrial dysfunction by inhibiting complex I and mimicking the key features of PD pathogenesis. This review focused on three main aspects of the MQC signaling pathways, that is, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy; hence, it demonstrates in detail how genetic and environmental factors result in PD pathogenesis by interfering with MQC pathways, thereby hopefully contributing to the discovery of novel potential therapeutic targets for PD.


Assuntos
Mitocôndrias/metabolismo , Doença de Parkinson/patologia , Humanos , Pessoa de Meia-Idade , Controle de Qualidade
6.
Immunopharmacol Immunotoxicol ; 41(4): 469-476, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31405314

RESUMO

The extracellular vesicles (EVs) represent a relatively new field of research in neurodegenerative disease and they are thought to be one of the ways that neurodegenerative pathologies, such as Parkinson's Disease (PD), spread in the brain. EVs are membrane vesicles released from cells into the extracellular space and they are produced by all cells of the nervous tissue. The classification of the vesicle subtypes comprises exosomes, microvesicles/microparticles, apoptotic bodies. EVs change in number and content in response to environmental conditions and may function as shuttles for the delivery of cargo between cells. Recent data suggest that exosomes secreted by both activated microglia and neurons play an important role in α-synuclein (α-syn) spreading and increase of neuroinflammation, thus exacerbating neuronal dysfunction and disease progression. α-syn is a presynaptic protein secreted by neurons in small amounts, and it is the main component of Lewy bodies, one of the histopathological features of PD. Several factors have shown to induce and/or modulate α-syn structure and oligomerization in vitro. Under pathological conditions, progressive accumulation of α-syn and the formation of oligomers have been proposed to play a critical role in the pathogenesis of PD. This review gives an overview about the multiple roles of exosomes in PD, despite their role in the progression of neurodegeneration, exosomes could represent a specific drug delivery tool for a difficult target such as the brain, which poses an obstacle to most drugs and they could also represent new biomarkers to track the progression of PD.


Assuntos
Exossomos/patologia , Doença de Parkinson/patologia , Animais , Biomarcadores/metabolismo , Progressão da Doença , Exossomos/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doença de Parkinson/metabolismo
7.
Neurology ; 93(7): 302-309, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31405935

RESUMO

OBJECTIVE: To test the hypothesis that myoclonus in patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) is associated with a heavier burden of α-synuclein deposition in the motor regions of the spinal cord, we compared the degree of α-synuclein deposition in spinal cords of 3 patients with MSA-C with myoclonus and 3 without myoclonus. METHODS: All human tissue was obtained by the Massachusetts General Hospital Department of Pathology with support from and according to neuropathology guidelines of the Massachusetts Alzheimer's Disease Research Center. Tissue was stained with Luxol fast blue and hematoxylin & eosin for morphologic evaluation, and with a mouse monoclonal antibody to α-synuclein and Vectastain DAB kit. Images of the spinal cord sections were digitized using a 10× objective lens. Grayscale versions of these images were transferred to ImageJ software for quantitative analysis of 8 different regions of interest (ROIs) in the spinal cord: dorsal column, anterior white column, left and right dorsal horns, left and right anterior horns, and left and right lateral corticospinal tracts. A mixed-effect, multiple linear regression model was constructed to determine if patients with and without myoclonus had significantly different distributions of α-synuclein deposition across the various ROIs. RESULTS: Patients with myoclonus had more α-synuclein in the anterior horns (p < 0.001) and lateral corticospinal tracts (p = 0.02) than those without myoclonus. CONCLUSIONS: In MSA-C, myoclonus appears to be associated with a higher burden of α-synuclein deposition within spinal cord motor regions. Future studies with more patients will be needed to confirm these findings.


Assuntos
Atrofia de Múltiplos Sistemas/patologia , Mioclonia/metabolismo , Medula Espinal/patologia , alfa-Sinucleína/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/complicações , Mioclonia/complicações , Doença de Parkinson/complicações , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Medula Espinal/metabolismo
8.
PLoS Genet ; 15(8): e1008352, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31449520

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Rare genetic mutations in genes such as Parkin, Pink1, DJ-1, α-synuclein, LRRK2 and GBA are found to be responsible for the disease in about 15% of the cases. A key unanswered question in PD pathophysiology is why would these mutations, impacting basic cellular processes such as mitochondrial function and neurotransmission, lead to selective degeneration of SNc DA neurons? We previously showed in vitro that SNc DA neurons have an extremely high rate of mitochondrial oxidative phosphorylation and ATP production, characteristics that appear to be the result of their highly complex axonal arborization. To test the hypothesis in vivo that axon arborization size is a key determinant of vulnerability, we selectively labeled SNc or VTA DA neurons using floxed YFP viral injections in DAT-cre mice and showed that SNc DA neurons have a much more arborized axon than those of the VTA. To further enhance this difference, which may represent a limiting factor in the basal vulnerability of these neurons, we selectively deleted in mice the DA D2 receptor (D2-cKO), a key negative regulator of the axonal arbour of DA neurons. In these mice, SNc DA neurons have a 2-fold larger axonal arborization, release less DA and are more vulnerable to a 6-OHDA lesion, but not to α-synuclein overexpression when compared to control SNc DA neurons. This work adds to the accumulating evidence that the axonal arborization size of SNc DA neurons plays a key role in their vulnerability in the context of PD.


Assuntos
Neurônios Dopaminérgicos/patologia , Plasticidade Neuronal/genética , Doença de Parkinson/patologia , Parte Compacta da Substância Negra/patologia , Receptores de Dopamina D2/genética , Animais , Axônios/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/patologia , Fosforilação Oxidativa , Doença de Parkinson/genética , Parte Compacta da Substância Negra/citologia , Receptores de Dopamina D2/metabolismo
9.
J Clin Neurosci ; 68: 235-242, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420273

RESUMO

This study used Voxel-based morphometry (VBM) and resting-state functional magnetic resonance imaging (rs-fMRI) to investigate changes in brain structure and networks functional connectivity, respectively. We tried to identify the potential biomarkers in Parkinson's disease (PD) progression. We recruited nine idiopathic PD patients and seven healthy control participants (HC group) who were age-matched to undergo T1-weighted images and rs-fMRI on 1.5 T. Brain structure differences were analyzed by VBM. Topological properties of networks functional connectivity were analyzed by graph theory. Thirty-two nodes of 8 networks and 133 nodes of interest then were identified with graph theory approaches. VBM examinations showed significant decreases of brain gray matter regions including the left temporal lobe, left middle temporal, middle temporal gyrus, parietal lobe, postcentral gyrus, left inferior parietal gyrus, medial frontal gyrus and supplement motor area in PD patients compared to the HC group. The 32 ROI of networks topological metrics measurement in PD demonstrated increases of global efficiency, cost, and degree in frontoparietal PPC (R) network, but decreases of local efficiency, clustering coefficient, and average path length in salience ACC, dorsal attention FEF (L), and salience aInsula (R) networks, respectively. All 165 ROI connectomes showed eight connections intensity changes, that decrease in OP r to frontoparietal PPC, putamen r to cereb11, and SFG l to Ver8 in PD. These results suggest that the graph theory and the network topological metrics measurement may be the potential biomarkers in PD to evaluate the disease progress and to monitor the therapeutic results.


Assuntos
Encéfalo/fisiopatologia , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Modelos Teóricos , Doença de Parkinson/fisiopatologia , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Conectoma/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Modelos Neurológicos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia
10.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416122

RESUMO

Accumulation of α-synuclein (α-Syn) is a remarkable pathology for Parkinson's disease (PD), therefore clearing it is possibly a promising strategy for treating PD. Aberrant copper (Cu(II)) homeostasis and oxidative stress play critical roles in the abnormal aggregation of α-Syn in the progress of PD. It is reported that the polyphenol (-)-epi-gallocatechin gallate (EGCG) can inhibit α-Syn fibrillation and aggregation, disaggregate α-Syn mature fibrils, as well as protect α-Syn overexpressed-PC12 cells against damage. Also, previous studies have reported that EGCG can chelate many divalent metal ions. What we investigate here is whether EGCG can interfere with the Cu(II) induced fibrillation of α-Syn and protect the cell viability. In this work, on a molecular and cellulaire basis, we demonstrated that EGCG can form a Cu(II)/EGCG complex, leading to the inhibition of Cu(II)-induced conformation transition of α-Syn from random coil to ß-sheet, which is a dominant structure in α-Syn fibrils and aggregates. Moreover, we found that the mixture of Cu(II) and EGCG in a molar ratio from 0.5 to 2 can efficiently inhibit this process. Furthermore, we demonstrated that in the α-Syn transduced-PC12 cells, EGCG can inhibit the overexpression and fibrillation of α-Syn in the cells, and reduce Cu(II)-induced reactive oxygen species (ROS), protecting the cells against Cu(II)-mediated toxicity.


Assuntos
Proteínas Amiloidogênicas/metabolismo , Catequina/análogos & derivados , Cobre , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Proteínas Amiloidogênicas/química , Animais , Catequina/química , Catequina/farmacologia , Linhagem Celular , Cobre/química , Cobre/toxicidade , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ressonância Magnética Nuclear Biomolecular , Estresse Oxidativo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/tratamento farmacológico , Ratos , Espécies Reativas de Oxigênio/metabolismo , alfa-Sinucleína/química
11.
Int J Mol Sci ; 20(15)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31382686

RESUMO

Lipids in the brain are major components playing structural functions as well as physiological roles in nerve cells, such as neural communication, neurogenesis, synaptic transmission, signal transduction, membrane compartmentalization, and regulation of gene expression. Determination of brain lipid composition may provide not only essential information about normal brain functioning, but also about changes with aging and diseases. Indeed, deregulations of specific lipid classes and lipid homeostasis have been demonstrated in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, recent studies have shown that membrane microdomains, named lipid rafts, may change their composition in correlation with neuronal impairment. Lipid rafts are key factors for signaling processes for cellular responses. Lipid alteration in these signaling platforms may correlate with abnormal protein distribution and aggregation, toxic cell signaling, and other neuropathological events related with these diseases. This review highlights the manner lipid changes in lipid rafts may participate in the modulation of neuropathological events related to AD and PD. Understanding and characterizing these changes may contribute to the development of novel and specific diagnostic and prognostic biomarkers in routinely clinical practice.


Assuntos
Envelhecimento/metabolismo , Lipídeos/genética , Microdomínios da Membrana/metabolismo , Doenças Neurodegenerativas/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Microdomínios da Membrana/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Transdução de Sinais/genética
13.
Artif Cells Nanomed Biotechnol ; 47(1): 2764-2774, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31298038

RESUMO

Parkinson's disease (PD) is a common age-related neurodegenerative disease resulted from the progressive degeneration of dopaminergic neurons in the pars compacta region of substantia nigra. The goal of this study was to investigate the effects and mechanisms of long noncoding RNA (lncRNA) HAGLROS on the apoptosis and autophagy in PD. The MPTP-induced PD mouse model and MPP+-intoxicated SH-SY5Y cell model were established, and the expression levels of HAGLROS and miR-100 were determined. Subsequently, the effects of suppression of HAGLROS on apoptosis and autophagy in MPTP-induced PD mouse model and in MPP+-intoxicated SH-SY5Y cells were investigated. In addition, the association between HAGLROS and miR-100 as well as HAGLROS and activation of phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in MPP+-intoxicated SH-SY5Y cells was explored. HAGLROS was increasingly expressed in MPTP-induced PD mouse model and MPP+-intoxicated SH-SY5Y cells and suppression of HAGLRO decreased apoptosis and autophagy in both in vivo and in vitro PD models. Further in vitro studies showed that HAGLRO negatively regulated miR-100 expression, and HAGLROS regulated apoptosis and autophagy of MPP+-intoxicated SH-SY5Y cells through sponging miR-100. Moreover, ATG10 was identified as a target of miR-100. Besides, suppression of HAGLROS alleviated MPP+-intoxicated SH-SY5Y cell injury by activating PI3K/AKT/mTOR pathway. Our findings reveal that upregulation of HAGLROS may contribute to the development of PD via inhibiting apoptosis and autophagy, which may be achieved by regulating miR-100/ATG10 axis and PI3K/AKT/mTOR pathway activation.


Assuntos
Apoptose/genética , Proteínas Relacionadas à Autofagia/genética , Autofagia/genética , MicroRNAs/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , RNA Longo não Codificante/genética , Proteínas de Transporte Vesicular/genética , Animais , Linhagem Celular Tumoral , Regulação da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo
14.
Brain Nerve ; 71(8): 875-883, 2019 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-31346144

RESUMO

Parkinson's disease (PD), a common neurodegenerative disorder, is characterized by selective degeneration of dopaminergic neurons in the substantia nigra. There is no effective treatment to delay or halt the progression of PD. The establishment of disease models, based on human biology, is therefore important for developing effective disease-modifying therapies. The recent progress of human induced pluripotent stem cell-associated technologies provides an opportunity to understand disease etiology, discover new drugs, and develop novel therapeutic interventions.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson/patologia , Neurônios Dopaminérgicos/patologia , Humanos , Modelos Biológicos , Substância Negra/patologia
15.
Nutrients ; 11(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331066

RESUMO

Vasicinone is a quinazoline alkaloid isolated from the Adhatoda vasica plant. In this study, we explored the neuroprotective effect and underlying molecular mechanism of vasicinone against paraquat-induced cellular apoptosis in SH-SY5Y cells. Vasicinone reduced the paraquat-induced loss of cell viability, rescued terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic nuclei, and suppressed generation of reactive oxygen species (ROS) in a dose-dependent manner. Western blotting analysis revealed that vasicinone increased the phosphorylation of IGF1R/PI3K/AKT cell survival signaling molecules and downregulated the paraquat-induced, mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)-mediated apoptotic pathways compared to that observed in cells not treated with vasicinone. This protection depended critically on the activation of IGF1R, and the silencing of IGF1R by siRNA completely abrogated the protective effect of vasicinone in SH-SY5Y cells. Our findings indicated that vasicinone is a potential candidate for the treatment of Parkinson's disease and possibly other oxidative stress-related neurodegenerative disorders.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Paraquat/farmacologia , Doença de Parkinson , Fosfatidilinositol 3-Quinases/metabolismo , Receptor IGF Tipo 1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Marcação In Situ das Extremidades Cortadas , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo
16.
Am J Occup Ther ; 73(4): 7304205050p1-7304205050p8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31318669

RESUMO

IMPORTANCE: Knowledge regarding the reliability of pegboard tests when used to measure dexterity in people with Parkinson's disease (PD) is currently limited. OBJECTIVE: To examine the test-retest and interrater reliability of the 9-Hole Peg Test (9HPT) and Purdue Pegboard Test (PPT) in people with PD. DESIGN: Cross-sectional observational study. For test-retest reliability, tests were completed on 2 days, 1 wk apart, in the "on" phase and "end-of-dose" period of participants' medication cycle. For interrater reliability, occupational therapists and physical therapists rated prerecorded pegboard test performance of participants with PD. SETTING: Test-retest reliability was determined in participants' homes or in a university department. Interrater reliability was determined in a university department or a hospital setting. PARTICIPANTS: Test-retest reliability was determined with volunteers diagnosed with PD (N = 30). Interrater reliability was determined with a convenience sample of occupational and physical therapists (N = 11). OUTCOMES AND MEASURES: The 9HPT and PPT are commonly used measures of manual dexterity. RESULTS: PPT subtests showed higher test-retest reliability (intraclass correlation coefficients [ICCs] ≥ .90) in both phases of the medication cycle compared with the 9HPT (ICCs = .70-.81). Minimal detectable change scores indicated acceptable measurement error for both tools. Interrater reliability for recorded performance of each measure was very good (ICCs > .99), with no calculable measurement error. CONCLUSIONS AND RELEVANCE: Although both tools showed adequate test-retest and interrater reliability, results suggest that the PPT may be a more reliable measure of dexterity loss in people with PD. WHAT THIS ARTICLE ADDS: This study informs the clinical measurement of the loss of manual dexterity in people with PD, a frequent problem reported by people living with this disorder.


Assuntos
Mãos/fisiopatologia , Doença de Parkinson/patologia , Estudos Transversais , Humanos , Reprodutibilidade dos Testes
17.
Expert Opin Pharmacother ; 20(15): 1847-1854, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31290336

RESUMO

Introduction: Pain is a common symptom in Parkinson's disease (PD), impairing quality of life. The clinical appearance and the underlying etiologies are diverse. Different subtypes of pain may occur, with musculoskeletal pain considered to be the most frequent. Often there is also a combination of different causes of pain. There is a lack of controlled studies addressing pain therapy in PD. Areas covered: In this review the authors analyzed the currently available data, taking into account the available publications in the databases, especially PubMed. The authors further provided their expert perspectives on the challenges of treating pain in PD patients. Expert opinion: There is both nociceptive and neuropathic pain and in patients with PD, some PD-related pain and some unrelated. Diagnosis requires a thorough and differentiated history and examination, and targeted diagnostics. Therapeutically, many drugs are used, but the data is unfortunately limited and not specific. Medications used include Parkinson-related, mainly dopaminergic drugs, as well as opioids and non-opioid analgetics, anticonvulsives, antidepressants, and more recently cannabinoids. Currently, therapy is performed nonspecifically, without taking into account the special requirements of PD. Unfortunately, in many cases, pain is resistant to these therapies. In the future, both diagnostic and therapeutic efforts should be made to address this issue.


Assuntos
Analgésicos Opioides/uso terapêutico , Neuralgia/tratamento farmacológico , Manejo da Dor/métodos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida/psicologia , Analgésicos Opioides/farmacologia , Humanos , Doença de Parkinson/patologia
18.
Int J Mol Sci ; 20(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277513

RESUMO

The main risk of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most common neurodegenerative pathologies, is aging. In contrast to sporadic cases, whose symptoms appear at >60 years of age, familial PD or familial AD affects younger individuals. Finding early biological markers of these diseases as well as efficacious treatments for both symptom relief and delaying disease progression are of paramount relevance. Familial early-onset PD/AD are due to genetic factors, sometimes a single mutation in a given gene. Both diseases have neuronal loss and abnormal accumulations of specific proteins in common, but in different brain regions. Despite shared features, the mechanisms underlying the pathophysiological processes are not known. This review aims at finding, among the genetic-associated cases of PD and AD, common trends that could be of interest to discover reliable biomarkers and efficacious therapies, especially those aimed at affording neuroprotection, i.e., the prevention of neuronal death.


Assuntos
Doença de Alzheimer/patologia , Neurônios/patologia , Doença de Parkinson/patologia , Doença de Alzheimer/genética , Morte Celular , Redes Reguladoras de Genes , Humanos , Mutação/genética , Doença de Parkinson/genética
19.
Chin Med J (Engl) ; 132(15): 1788-1795, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31283653

RESUMO

BACKGROUND: Sleep disorders are one of the earliest non-motor symptoms of Parkinson's disease (PD). Sleep disorders could, therefore, have value for recognition and diagnosis in PD. However, no unified classification and diagnostic criteria exist to evaluate sleep disorders by polysomnography (PSG). Utilizing PSG to monitor sleep processes of patients with PD and analyze sleep disorder characteristics and their relationship with demographic parameters could aid in bridging this gap. This preliminary study aimed to evaluate the clinical characteristic of sleep disorders in PD using PSG. METHODS: PSG was used to evaluate sleep disorders in 27 patients with PD and 20 healthy volunteers between August 2015 and July 2018 in Fujian Medical University Union Hospital. Total sleep time (TST), sleep efficiency (SE), total wake time, and other parameters were compared between the two groups. Finally, the correlation between sleep disorders and age, disease duration, Unified Parkinson's Disease Rating Scale-III scores, Hoehn-Yahr stage, and levodopa dose were analyzed. The main statistical methods included Chi-square test, two independent samples t test, Fisher exact test, and Pearson correlation. RESULTS: Sleep fragmentation in the PD group was significantly increased (74.1%) while difficulty falling asleep and early awakening were not, as compared to healthy controls. No significant differences were found in time in bed, sleep latency (SL), non-rapid eye movement (NREM) stage 1 (N1), N1%, N2, N2%, N3%, and NREM% between PD and control groups; but TST (327.96 ±â€Š105.26 min vs. 414.67 ±â€Š78.31 min, P = 0.003), SE (63.26% ±â€Š14.83% vs. 76.8% ±â€Š11.57%, P = 0.001), R N3 (20.00 [39.00] min vs. 61.50 [48.87] min, P = 0.001), NREM (262.59 ±â€Š91.20 min vs. 337.17 ±â€Š63.47 min, P = 0.003), rapid-eye-movement (REM) (32.50 [33.00] min vs. 85.25 [32.12] min, P < 0.001), REM% (9.56 ±â€Š6.01 vs. 15.50 ±â€Š4.81, P = 0.001), REM sleep latency (157.89 ±â€Š99.04 min vs. 103.47 ±â€Š71.70 min, P = 0.034) were significantly reduced in PD group. CONCLUSION: This preliminary study supported that sleep fragmentation was an important clinical characteristic of sleep disorders in PD. Whether sleep fragmentation is a potential quantifiable marker in PD needs to be further investigated in the future study.


Assuntos
Doença de Parkinson/patologia , Privação do Sono/patologia , Transtornos do Sono-Vigília/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Polissonografia , Privação do Sono/fisiopatologia , Transtornos do Sono-Vigília/fisiopatologia , Sono REM/fisiologia
20.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340557

RESUMO

Background: Several biophysical techniques have been successfully implemented to detect G protein-coupled receptors (GPCRs) heteromerization. Although these approaches have made it possible to ascertain the presence of GPCR heteromers in animal models of disease, no success has been accomplished in pathological human post-mortem brains. The AlphaScreen technology has been consistently used to quantify small analyte accumulation or depletion, bimolecular interactions, and post-translational modifications. The high signal-to-background, dynamic range and sensitivity exhibited by this technology support that it may be suitable to detect GPCR heteromers even under non-optimal conditions. Methods: Here, we describe the development of a new AlphaScreen assay to detect GPCR oligomers in human post-mortem brain. Results: Adenosine A2A-dopamine D2 receptor (A2AR/D2R) heteromer formation was monitored in caudate from healthy and Parkinson's disease (PD) subjects. The approach was first validated using striatal membranes from wild type and A2AR deficient mice. Secondly, we took advantage of the 6-hydroxydopamine hemiparkinsonian rat model to validate previous results. In addition, finally, A2AR/D2R heteromer formation was assessed in caudate membranes from human post-mortem brains. Importantly, our preliminary results revealed an increase in A2AR/D2R heteromer formation in PD brains. Conclusions: The new AlphaScreen assay allowed assessing GPCR heteromers in human post-mortem brains with high sensitivity.


Assuntos
Autopsia/métodos , Corpo Estriado/metabolismo , Ensaios de Triagem em Larga Escala/instrumentação , Doença de Parkinson Secundária/genética , Doença de Parkinson/genética , Receptor A2A de Adenosina/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Autopsia/instrumentação , Estudos de Casos e Controles , Corpo Estriado/patologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Oxidopamina/administração & dosagem , Doença de Parkinson/diagnóstico , Doença de Parkinson/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Multimerização Proteica , Ratos , Ratos Sprague-Dawley , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo
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