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1.
Med Sci Monit ; 26: e930340, 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33323916

RESUMO

Alterations in complex behavioral patterns during the extended period of the COVID-19 pandemic are predicted to promote a variety of psychiatric disease symptoms due to enforced social isolation and self-quarantine. Accordingly, multifaceted mental health problems will continue to increase, thereby creating a challenge for society and the health care system in general. Recent studies show that COVID-19 can directly or indirectly influence the central nervous system, potentially causing neurological pathologies such as Alzheimer disease and Parkinson disease. Thus, chronic COVID-19-related disease processes have the potential to cause serious mental illnesses, including depression, anxiety, and sleep disorders. Importantly, mental health problems can foster systemic changes in functionally-linked neuroendocrine conditions that heighten a person's susceptibility to COVID-19 infection. These altered defense mechanisms may include compromised "self-control" and "self-care", as well as a "lack of insight" into the danger posed by the virus. These consequences may have serious social impacts on the future of COVID-19 survivors. Compounding the functionally related issues of altered mental health parameters and viral susceptibility are the potential effects of compromised immunity on the establishment of functional herd immunity. Within this context, mental health takes on added importance, particularly in terms of the need to increase support for mental health research and community-based initiatives. Thus, COVID-19 infections continue to reveal mental health targets, a process we must now be prepared to deal with.


Assuntos
/complicações , Saúde Mental , Sobreviventes/psicologia , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/virologia , Ansiedade/epidemiologia , Ansiedade/prevenção & controle , Ansiedade/psicologia , /psicologia , Depressão/epidemiologia , Depressão/prevenção & controle , Depressão/psicologia , Suscetibilidade a Doenças/psicologia , Humanos , Pandemias , Doença de Parkinson/epidemiologia , Doença de Parkinson/prevenção & controle , Doença de Parkinson/virologia , Autocuidado/psicologia , Autocontrole/psicologia , Isolamento Social/psicologia
2.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276415

RESUMO

Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer's and Parkinson's disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism Caenorhabditis elegans was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different C. elegans PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.


Assuntos
Acetatos/uso terapêutico , Monoterpenos Ciclopentânicos/uso terapêutico , Neurônios Dopaminérgicos/metabolismo , Doença de Parkinson/prevenção & controle , Álcool Feniletílico/análogos & derivados , Piranos/uso terapêutico , alfa-Sinucleína , Acetatos/farmacologia , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/efeitos dos fármacos , Monoterpenos Ciclopentânicos/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/fisiologia , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Polifenóis/farmacologia , Piranos/farmacologia , Resultado do Tratamento
3.
Neurobiol Aging ; 89: 12-23, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32143981

RESUMO

The nigrostriatal dopaminergic system (NDS) controls motor activity, and its impairment during type 2 diabetes (T2D) progression could increase Parkinson's disease risk in diabetics. If so, whether glycemia regulation prevents this impairment needs to be addressed. We investigated whether T2D impairs the NDS and whether dipeptidyl peptidase-4 inhibition (DPP-4i; a clinical strategy against T2D but also neuroprotective in animal models) prevents this effect, in middle-aged mice. Neither T2D (induced by 12 months of high-fat diet) nor aging (14 months) changed striatal dopamine content assessed by high-performance liquid chromatography. However, T2D reduced basal and amphetamine-stimulated striatal extracellular dopamine, assessed by microdialysis. Both the DPP-4i linagliptin and the sulfonylurea glimepiride (an antidiabetic comparator unrelated to DPP-4i) counteracted these effects. The functional T2D-induced effects did not correlate with NDS neuronal/glial alterations. However, aging itself affected striatal neurons/glia, and the glia effects were counteracted mainly by DPP-4i. These findings show NDS functional pathophysiology in T2D and suggest the preventive use of two unrelated anti-T2D drugs. Moreover, DPP-4i counteracted striatal age-related glial alterations suggesting striatal rejuvenation properties.


Assuntos
Envelhecimento/metabolismo , Corpo Estriado/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Dopamina/metabolismo , Linagliptina/farmacologia , Substância Negra/metabolismo , Compostos de Sulfonilureia/farmacologia , Animais , Diabetes Mellitus Tipo 2/complicações , Progressão da Doença , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Doença de Parkinson/etiologia , Doença de Parkinson/prevenção & controle , Risco
4.
Sci Rep ; 10(1): 5284, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210343

RESUMO

Although the malfunction of HtrA2/Omi leads to Parkinson's disease (PD), the underlying mechanism has remained unknown. Here, we showed that HtrA2/Omi specifically removed oligomeric α-Syn but not monomeric α-Syn to protect oligomeric α-Syn-induced neurodegeneration. Experiments using mnd2 mice indicated that HtrA2/Omi degraded oligomeric α-Syn specifically without affecting monomers. Transgenic Drosophila melanogaster experiments of the co-expression α-Syn and HtrA2/Omi and expression of genes individually also confirmed that pan-neuronal expression of HtrA2/Omi completely rescued Parkinsonism in the α-Syn-induced PD Drosophila model by specifically removing oligomeric α-Syn. HtrA2/Omi maintained the health and integrity of the brain and extended the life span of transgenic flies. Because HtrA2/Omi specifically degraded oligomeric α-Syn, co-expression of HtrA2/Omi and α-Syn in Drosophila eye maintained a healthy retina, while the expression of α-Syn induced retinal degeneration. This work showed that the bacterial function of HtrA to degrade toxic misfolded proteins is evolutionarily conserved in mammalian brains as HtrA2/Omi.


Assuntos
Encéfalo/metabolismo , Serina Peptidase 2 de Requerimento de Alta Temperatura A/metabolismo , Neurônios/metabolismo , Doença de Parkinson/prevenção & controle , alfa-Sinucleína/metabolismo , Animais , Animais Geneticamente Modificados , Encéfalo/patologia , Modelos Animais de Doenças , Drosophila melanogaster , Feminino , Serina Peptidase 2 de Requerimento de Alta Temperatura A/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/genética
5.
Oxid Med Cell Longev ; 2020: 4293071, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215173

RESUMO

Aim: This study was aimed at investigating the effects and molecular mechanisms of physical activity intervention on Parkinson's disease (PD) and providing theoretical guidance for the prevention and treatment of PD. Methods: Four electronic databases up to December 2019 were searched (PubMed, Springer, Elsevier, and Wiley database), 176 articles were selected. Literature data were analyzed by the logic analysis method. Results: (1) Risk factors of PD include dairy products, pesticides, traumatic brain injury, and obesity. Protective factors include alcohol, tobacco, coffee, black tea, and physical activity. (2) Physical activity can reduce the risk and improve symptoms of PD and the beneficial forms of physical activity, including running, dancing, traditional Chinese martial arts, yoga, and weight training. (3) Different forms of physical activity alleviate the symptoms of PD through different mechanisms, including reducing the accumulation of α-syn protein, inflammation, and oxidative stress, while enhancing BDNF activity, nerve regeneration, and mitochondrial function. Conclusion: Physical activity has a positive impact on the prevention and treatment of PD. Illustrating the molecular mechanism of physical activity-induced protective effect on PD is an urgent need for improving the efficacy of PD therapy regimens in the future.


Assuntos
Exercício Físico/fisiologia , Doença de Parkinson/prevenção & controle , Doença de Parkinson/terapia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Terapia por Exercício , Humanos , Inflamação/prevenção & controle , Mitocôndrias/fisiologia , Estresse Oxidativo/fisiologia , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia , Fatores de Risco , alfa-Sinucleína/metabolismo
6.
Int J Mol Sci ; 21(4)2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32098449

RESUMO

Abstract: TFEB (transcription factor EB), which is a master regulator of autophagy and lysosome biogenesis, is considered to be a new therapeutic target for Parkinson's disease (PD). However, only several small-molecule TFEB activators have been discovered and their neuroprotective effects in PD are unclear. In this study, a curcumin derivative, named E4, was identified as a potent TFEB activator. Compound E4 promoted the translocation of TFEB from cytoplasm into nucleus, accompanied by enhanced autophagy and lysosomal biogenesis. Moreover, TFEB knockdown effectively attenuated E4-induced autophagy and lysosomal biogenesis. Mechanistically, E4-induced TFEB activation is mainly through AKT-MTORC1 inhibition. In the PD cell models, E4 promoted the degradation of α-synuclein and protected against the cytotoxicity of MPP+ (1-methyl-4-phenylpyridinium ion) in neuronal cells. Overall, the TFEB activator E4 deserves further study in animal models of neurodegenerative diseases, including PD.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Curcumina/farmacologia , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/metabolismo , 1-Metil-4-fenilpiridínio/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Células HeLa , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/prevenção & controle , Neurônios/citologia , Neurônios/efeitos dos fármacos , Células PC12 , Doença de Parkinson/genética , Doença de Parkinson/prevenção & controle , Interferência de RNA , Ratos , Transdução de Sinais/efeitos dos fármacos , alfa-Sinucleína/metabolismo
7.
BMC Med Inform Decis Mak ; 20(1): 34, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075633

RESUMO

BACKGROUND: Despite the established evidence and theoretical advances explaining human judgments under uncertainty, developments of mobile health (mHealth) Clinical Decision Support Systems (CDSS) have not explicitly applied the psychology of decision making to the study of user needs. We report on a user needs approach to develop a prototype of a mHealth CDSS for Parkinson's disease (PD), which is theoretically grounded in the psychological literature about expert decision making and judgement under uncertainty. METHODS: A suite of user needs studies was conducted in 4 European countries (Greece, Italy, Slovenia, the UK) prior to the development of PD_Manager, a mHealth-based CDSS designed for Parkinson's disease, using wireless technology. Study 1 undertook Hierarchical Task Analysis (HTA) including elicitation of user needs, cognitive demands and perceived risks/benefits (ethical considerations) associated with the proposed CDSS, through structured interviews of prescribing clinicians (N = 47). Study 2 carried out computational modelling of prescribing clinicians' (N = 12) decision strategies based on social judgment theory. Study 3 was a vignette study of prescribing clinicians' (N = 18) willingness to change treatment based on either self-reported symptoms data, devices-generated symptoms data or combinations of both. RESULTS: Study 1 indicated that system development should move away from the traditional silos of 'motor' and 'non-motor' symptom evaluations and suggest that presenting data on symptoms according to goal-based domains would be the most beneficial approach, the most important being patients' overall Quality of Life (QoL). The computational modelling in Study 2 extrapolated different factor combinations when making judgements about different questions. Study 3 indicated that the clinicians were equally likely to change the care plan based on information about the change in the patient's condition from the patient's self-report and the wearable devices. CONCLUSIONS: Based on our approach, we could formulate the following principles of mHealth design: 1) enabling shared decision making between the clinician, patient and the carer; 2) flexibility that accounts for diagnostic and treatment variation among clinicians; 3) monitoring of information integration from multiple sources. Our approach highlighted the central importance of the patient-clinician relationship in clinical decision making and the relevance of theoretical as opposed to algorithm (technology)-based modelling of human judgment.


Assuntos
Tomada de Decisão Clínica , Sistemas de Apoio a Decisões Clínicas , Pessoal de Saúde/psicologia , Doença de Parkinson/prevenção & controle , Telemedicina , Grécia , Humanos , Itália , Julgamento , Modelos Teóricos , Teoria Psicológica , Eslovênia , Reino Unido
9.
Biochem Pharmacol ; 173: 113722, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31756328

RESUMO

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in the elderly people. To date, drugs able to reverse the disease are not available; the gold standard is levodopa that only relieves clinical symptoms, yet with severe side effects after prolonged administration. Many efforts are underway to find alternative targets for PD prevention or treatment, the most promising being α-synuclein (Syn). Recently, we reported that oleuropein aglycone (OleA) interferes with amyloid aggregation of Syn both stabilizing its monomeric state and inducing the formation of harmless, off-pathway oligomers. This study is focused at describing the interaction between Syn and hydroxytyrosol (HT), the phenolic moiety and main metabolite of OleA, and the interferences with Syn aggregation by using biophysical and biological techniques. Our results show that HT dose-dependently inhibits Syn aggregation and that covalent and non-covalent binding mediate HT-Syn interaction. HT does not modify the natively unfolded structure of Syn, rather, it stabilizes specific regions of the molecule leading to inhibition of protein fibrillation. Cellular assays showed that HT reduces the toxicity of Syn aggregates. Moreover, Syn aggregates interaction with the cell membrane, an important factor for prion-like properties of Syn on-pathway oligomers, was reduced in cells exposed to Syn aggregates grown in the presence of HT.


Assuntos
Doença de Parkinson/prevenção & controle , Álcool Feniletílico/análogos & derivados , Agregação Patológica de Proteínas/prevenção & controle , alfa-Sinucleína/química , Acetatos/química , Acetatos/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antiparkinsonianos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Monoterpenos Ciclopentânicos/química , Monoterpenos Ciclopentânicos/metabolismo , Humanos , Levodopa/farmacologia , Estrutura Molecular , Doença de Parkinson/metabolismo , Álcool Feniletílico/química , Álcool Feniletílico/metabolismo , Álcool Feniletílico/farmacologia , Agregação Patológica de Proteínas/metabolismo , Ligação Proteica/efeitos dos fármacos , Conformação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Piranos/química , Piranos/metabolismo , alfa-Sinucleína/metabolismo
10.
Oxid Med Cell Longev ; 2019: 8169125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827703

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer's disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3ß and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.


Assuntos
Adrenérgicos/toxicidade , Modelos Animais de Doenças , Hidrazonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Doença de Parkinson/prevenção & controle , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Biogênese de Organelas , Consumo de Oxigênio/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia
11.
Arch Pharm Res ; 42(12): 1081-1091, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31705299

RESUMO

Daidzein, one of the important isoflavones, is extensively metabolized in the human body following consumption. In particular, 6,7,4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, has been the focus of recent investigations due to its various health benefits, such as anti-cancer and anti-obesity effects. However, the protective effects of 6,7,4'-THIF have not yet been studied in models of Parkinson's disease (PD). Therefore, the present study aimed to investigate the protective activity of 6,7,4'-THIF on 6-hydroxydopamine (OHDA)-induced neurotoxicity in SH-SY5Y human neuroblastoma cells. Pretreatment of SH-SY5Y cells with 6,7,4'-THIF significantly inhibited 6-OHDA-induced neuronal cell death, lactate dehydrogenase release, and reactive oxygen species production. In addition, 6,7,4'-THIF significantly attenuated reductions in 6-OHDA-induced superoxide dismutase activity and glutathione content. Moreover, 6,7,4'-THIF attenuated alterations in Bax and Bcl-2 expression and caspase-3 activity in 6-OHDA-induced SH-SY5Y cells. Furthermore, 6,7,4'-THIF significantly reduced 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase 1/2. Additionally, 6,7,4'-THIF effectively prevented 6-OHDA-induced loss of tyrosine hydroxylase. Taken together, these results suggest that 6,7,4'-THIF, a major metabolite of daidzein, may be an attractive option for treating and/or preventing neurodegenerative disorders such as PD.


Assuntos
Antineoplásicos/farmacologia , Isoflavonas/metabolismo , Isoflavonas/farmacologia , Neuroblastoma/tratamento farmacológico , Neurônios/efeitos dos fármacos , Oxidopamina/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/metabolismo , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoflavonas/química , Estrutura Molecular , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/farmacologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/prevenção & controle , Células Tumorais Cultivadas
12.
Aging (Albany NY) ; 11(21): 9424-9441, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31697645

RESUMO

Mitochondrial dysfunction and oxidative damage are closely related to the pathogenesis of Parkinson's disease (PD). The pharmacological mechanism of protocatechuic aldehyde (PCA) for PD treatment have retained unclear. The purposes of the present study were to clarify the neuroprotective effects of post-treatment of PCA for PD treatment by mitigating mitochondrial dysfunction and oxidative damage, and to further determine whether its effects were mediated by the polo-like kinase 2/phosphorylated glycogen synthase kinase 3 ß/nuclear factor erythroid-2-related factor 2 (PLK2/p-GSK3ß/Nrf2) pathways. We found that PCA improved 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic cell loss. Moreover, PCA increased the expressions of PLK2, p-GSK3ß and Nrf2, following the decrease of α-synuclein (α-Syn) in MPTP-intoxicated mice. Cell viability was increased and the apoptosis rate was reduced by PCA in 1-methyl-4-phenylpyridinium iodide (MPP+)-incubated cells. Mitochondrial membrane potential (MMP), mitochondrial complex I activity and reactive oxygen species (ROS) levels in MPP+-incubated cells were also ameliorated by treatment with PCA. The neuroprotective effects of PCA were abolished by inhibition or knockdown of PLK2, whereas overexpression of PLK2 strengthened the protection of PCA. Furthermore, GSK3ß and Nrf2 were involved in PCA-induced protection. These results indicated that PCA has therapeutic effects on PD by the PLK2/p-GSK3ß/Nrf2 pathway.


Assuntos
Benzaldeídos/farmacologia , Catecóis/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/prevenção & controle , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzaldeídos/uso terapêutico , Catecóis/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/metabolismo , Fitoterapia , Salvia miltiorrhiza , Transdução de Sinais/efeitos dos fármacos
13.
Cells ; 8(11)2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31671704

RESUMO

: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Células-Tronco Embrionárias/citologia , Células-Tronco Mesenquimais/citologia , Degeneração Neural , Células-Tronco Neurais/citologia , Doença de Parkinson/prevenção & controle , Transplante de Células-Tronco/métodos , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurotoxinas/toxicidade , Estresse Oxidativo , Doença de Parkinson/etiologia , Doença de Parkinson/patologia
14.
Int Rev Neurobiol ; 147: 45-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607362

RESUMO

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the world. Unfortunately, most of the currently used clinical therapies against PD are symptomatic and there is still no remedy can stop disease progression. Collective evidence shows that various kinds of exercise may reduce the risk of PD and do have positive impacts on both motor and nonmotor symptoms of PD. Additionally, exercise can also ameliorate the side effects such as wearing-off and dyskinesia induced by anti-PD therapeutics. In parallel with its benefits in ameliorating clinical symptoms, exercise modulates a range of supporting systems for brain maintenance and plasticity including neurogenesis, synaptogenesis, enhanced metabolism and angiogenesis. Exercise provides all these broad benefits on PD through inhibiting oxidative stress, repairing mitochondrial damage, and promoting the production of growth factors. Moreover, exercise reduces risk of other geriatric diseases such as diabetes, hypertension and cardiovascular disease, which may also contribute to PD pathogenesis. In summary, exercise is increasingly considered to be a complementary strategy to PD medications. In this chapter, we summarize the recent research progress on the beneficial effects of exercise on PD, discuss the underlying mechanisms, and highlight the promising prospects of exercise for antiparkinsonian therapy.


Assuntos
Terapia por Exercício , Exercício Físico/fisiologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Animais , Modelos Animais de Doenças , Humanos , Doença de Parkinson/prevenção & controle , Condicionamento Físico Animal/fisiologia
15.
PLoS One ; 14(10): e0224236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31639149

RESUMO

BACKGROUND: It has been found that thiazolidinediones (TZDs) may play a protective role in animal models of Parkinson's disease (PD), while the results remain controversial whether TZDs protect against Parkinson's disease in humans. The purpose of this meta-analysis is to explore the association between TZDs use and the incidence of PD in diabetic patients. METHODS: A systematic online search was conducted to find studies published up to 31 December 2018. In our exploratory meta-analysis, studies comparing incidence of PD between TZD-treated and non-TZD-treated groups of diabetic patients were included. Data analysis was performed using a random or fixed effects model and expressed as odds ratios (OR) with 95% confidence interval (95% CI). We used the Cochrane Collaboration's Review Manager 5.3 software to analyze data. RESULTS: In total, 5 retrospective observational cohort studies were identified which met the inclusion criteria. The pooled odds ratio (OR) was 0.70 [95% CI, 0.51 to 0.96; p = 0.03] in a random-effects model, indicating a 30% lower risk of developing PD in diabetic patients treated with TZDs compared with non-TZD-treated patients. CONCLUSION: In this exploratory meta-analysis, we found that TZDs use was associated with reduced risk of PD in diabetic patients. However, this meta-analysis was not registered online although we followed a protocol designed for it. Further prospective observational studies with larger sample size and more strict inclusion criteria including controlling for diabetes complication severity index, hypoglycemic drugs combination, sex ratio, and comorbidity are needed to guide whether RCTs are warranted. And RCTs can better determine whether TZDs use could lower incidence of PD in diabetic patients.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Doença de Parkinson/prevenção & controle , Tiazolidinedionas/uso terapêutico , Humanos , Doença de Parkinson/etiologia , Prognóstico , Comportamento de Redução do Risco
16.
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
17.
Eur J Pharmacol ; 862: 172639, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491406

RESUMO

This study investigated the effect of dextromethorphan (DXM) against Parkinson's disease (PD) in rats and explored the association between DXM dose and PD risk in elderly patients 65 years and older using a population-based database. The PD rat model (Sprague Dawley rats) was induced by injecting 6-hydroxydopamine (6-OHDA) into the unilateral medial forebrain bundle of the rat brain. DXM (20 mg/kg) was administered intraperitoneally twice daily from 7 days before the appearance of a 6-OHDA lesion to 28 days after the lesion appeared. The availability of dopamine transporter (DAT) and serotonin transporter (SERT) in the striatum of the rat brain was measured using positron emission tomography. The apomorphine-induced rotation test was performed to study the hypersensitivity of the brain regions with lesions. This animal study demonstrated that DXM significantly attenuated 6-OHDA-induced DAT and SERT loss, correlating to rotational behaviors. The population-based human study analyzed the data from the Taiwan Longitudinal Health Insurance Database 2005 between January 2005 and December 2013 and then used the DXM dose-response curve to investigate the trend of its protective effect against PD. In the human study, low cumulative doses of DXM may potentially achieve a protective effect for PD; however, high cumulative doses seem to be a risk for PD.


Assuntos
Dextrometorfano/administração & dosagem , Doença de Parkinson Secundária/prevenção & controle , Doença de Parkinson/prevenção & controle , Substâncias Protetoras/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Estudos de Casos e Controles , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/análise , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Oxidopamina/toxicidade , Doença de Parkinson/epidemiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/análise , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Taiwan/epidemiologia , Microtomografia por Raio-X
18.
PLoS One ; 14(8): e0220849, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393918

RESUMO

Mutations in ATP13A2 cause Kufor-Rakeb syndrome (KRS), a juvenile form of Parkinson's disease (PD) with dementia. However, the mechanisms by which mutations in ATP13A2 cause KRS is not understood. The mutations lead to misfolding of the translated Atp13a2 protein and its premature degradation in the endoplasmic reticulum, never reaching the lysosome where the protein is thought to function. Atp13a2 is a P-type ATPase, a class of proteins that function in ion transport. Indeed, studies of human, mouse, and yeast Atp13a2 proteins suggest a possible involvement in regulation of heavy metal toxicity. Here we report on the cytoprotective function of Atp13a2 on HeLa cells and dopamine neurons of Caenorhabditis elegans (C. elegans). HeLa cells stably overexpressing V5- tagged Atp13a2Isoform-1 protein were more resistant to elevated manganese exposure and to starvation-induced cell death compared to cells not overexpressing the protein. Because PD is characterized by loss of dopamine neurons, we generated transgenic C. elegans expressing GFP-tagged human Atp13a2 protein in dopamine neurons. The transgenic animals exhibited higher resistance to dopamine neuron degeneration after acute exposure to manganese compared to nematodes that expressed GFP alone. The results suggest Atp13a2 Isoform-1 protein confers cytoprotection against toxic insults, including those that cause PD syndromes.


Assuntos
Morte Celular , Manganês/toxicidade , ATPases Translocadoras de Prótons/farmacologia , Inanição , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Células HeLa , Humanos , Doença de Parkinson/prevenção & controle , Substâncias Protetoras/metabolismo , Isoformas de Proteínas , ATPases Translocadoras de Prótons/genética , ATPases Translocadoras de Prótons/metabolismo
19.
Med Hypotheses ; 131: 109302, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443765

RESUMO

Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. ß-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. ß-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and ß-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, ß-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of ß-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 ß (GSK-3ß). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3ß inhibition and consequent enhanced ß-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect ß-catenin-mediated activity and slow disease progression in patients with PD or melanoma.


Assuntos
Lítio/farmacologia , Melanoma/prevenção & controle , Modelos Biológicos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/prevenção & controle , Fumantes , Tabaco/química , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/prevenção & controle , Autofagia/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/fisiologia , Humanos , Incidência , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lítio/análise , Lítio/uso terapêutico , Carbonato de Lítio/uso terapêutico , Melanoma/epidemiologia , Mutação , Fármacos Neuroprotetores/análise , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Doença de Parkinson/epidemiologia , Transtornos Parkinsonianos/tratamento farmacológico , Água/química , Via de Sinalização Wnt/fisiologia , alfa-Sinucleína/metabolismo , beta-Glucosidase/genética
20.
Nutrients ; 11(8)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416163

RESUMO

Parkinson's disease (PD) is a frequent neurodegenerative disease among elderly people. Genetic and underlying environmental factors seem to be involved in the pathogenesis of PD related to degeneration of dopaminergic neurons in the striatum. In previous experimental researches oxidative stress, mitochondrial dysfunction, homocysteine, and neuroinflammation have been reported as potential mechanisms. Among environmental factors, nutrition is one of the most investigated areas as it is a potentially modifiable factor. The purpose of this review is to provide current knowledge regarding the relation between diet and PD risk. We performed a comprehensive review including the most relevant studies from the year 2000 onwards including prospective studies, nested case-control studies, and meta-analysis. Among dietary factors we focused on specific nutrients and food groups, alcoholic beverages, uric acid, and dietary patterns. Furthermore, we included studies on microbiota as recent findings have shown a possible impact on neurodegeneration. As a conclusion, there are still many controversies regarding the relationship between PD and diet which, beside methodological differences among studies, may be due to underlying genetic and gender-specific factors. However, some evidence exists regarding a potential protective effect of uric acid, poly-unsaturated fatty acids, coffee, and tea but mainly in men, whereas dairy products, particularly milk, might increase PD risk through contaminant mediated effect.


Assuntos
Dieta , Microbioma Gastrointestinal , Estado Nutricional , Doença de Parkinson/epidemiologia , Dieta/efeitos adversos , Dieta Saudável , Comportamento Alimentar , Interações Hospedeiro-Patógeno , Humanos , Valor Nutritivo , Doença de Parkinson/microbiologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/prevenção & controle , Fatores de Proteção , Medição de Risco , Fatores de Risco
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