Altered dopamine metabolism and its role in pathogenesis of Parkinson's disease / 生理学报

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). Genetic vulnerability, aging, environmental insults are believed to contribute to the pathogenesis of PD. However, the cellular and molecular mechanism of dopaminergic neurons degeneration remains incompletely understood. Dopamine (DA) metabolism is a cardinal physiological process in dopaminergic neurons, which is closely related to the loss of dopaminergic neurons in the SN. DA metabolism takes part in several pathological processes of PD neurodegeneration, such as iron metabolism disturbance, α-synuclein mis-folding, endoplasmic reticulum stress, protein degradation dysfunction, neuroinflammatory response, etc. In this review, we will describe altered DA metabolism and its contributions to PD pathogenesis.

Relação entre estilo de vida e a etiologia da doença de Parkinson em pacientes do Município de Jequié ­ BA / Relationship between lifestyle and etiology of Parkinson disease in patients of Jequié ­ Municipality

A doença de Parkinson (DP) consiste de uma alteração neurológica decorrente da destruição generalizada de parte da substantia nigra, dos gânglios basais, onde se localizam os neurônios dopaminérgicos, que por fatores ainda não muito esclarecidos se degeneram. É considerada uma moléstia idiopática, possivelmente multifatorial, e de incidência relativamente alta, justificando mais estudos sobre esse assunto. OBJETIVO: analisar a relação entre o estilo de vida e a etiologia da Doença de Parkinson em pacientes do município de Jequié - BA, correlacionando o estilo de vida desses indivíduos com o desenvolvimento da Doença de Parkinson. MÉTODOS: Trata-se de um estudo do tipo caso-controle, com um desenho observacional, analítico e transversal de base populacional, que envolveu a identificação de indivíduos portadores (casos) e não portadores (controles) da Doença de Parkinson. Uma amostra de 38 participantes, tendo por casos 17 indivíduos diagnosticados com DP casos e 21 controles. O estilo de vida foi avaliado, relacionando com possíveis fatores de risco e proteção. RESULTADOS: Verificamos diferenças estatisticamente significativas para a exposição à praguicidas (p = 0,03), consumo de água de poço (p < 0,0001), uso continuado de medicamentos (p = 0,02), ao consumo de carne vermelha (p = 0,01), ao histórico familiar de DP (p = 0,004), todos apontados como fatores de risco, enquanto que apenas a carga tabágica de 50 cigarros/ano/dia mostrou diferença estaticamente significativa (p = 0,0002), sendo associada como fator protetor. CONCLUSÃO: Esses resultados parecem consistentes com a literatura atual, que sugere um modelo multifatorial para etiologia da DP.

Parkinson's disease (PD) consists of a neurological alteration resulting from the widespread destruction of part of the substantia nigra, of the basal ganglia, where dopaminergic neurons are located, which, due to factors not yet well understood, degenerate. It is considered an idiopathic disease, possibly multifactorial, and of relatively high incidence, justifying further studies on this subject. OBJECTIVE: to analyze the relationship between lifestyle and the etiology of Parkinson's Disease in patients from the municipality of Jequié - BA, correlating the lifestyle of these individuals with the development of Parkinson's Disease. METHODS: This is a case-control study with an observational, analytical, cross-sectional population-based design that involved the identification of individuals (cases) and non-carriers (controls) of Parkinson's Disease. A sample of 38 participants, having 17 cases diagnosed with PD cases and 21 controls. Lifestyle was assessed, relating to possible risk factors and protection. RESULTS: We found statistically significant differences for pesticide exposure (p = 0.03), well water consumption (p <0.0001), continued use of medications (p =0.02), and red meat consumption ( p = 0.01), the family history of PD (p = 0.004), all of which were identified as risk factors, whereas only the tabacic load of 50 cigarettes / year / day showed a statistically significant difference (p = 0.0002), being associated as a protective factor. CONCLUSION: These results seem consistent with the current literature, which suggests a multifactorial model for the etiology of PD.

Does Parkinson's disease start in the gut? / A doença de Parkinson começa no intestino?

ABSTRACT Current understanding of the pathophysiology of Parkinson's disease suggests a key role of the accumulation of alpha-synuclein in the pathogenesis. This critical review highlights major landmarks, hypotheses and controversies about the origin and progression of synucleinopathy in Parkinson's disease, leading to an updated review of evidence suggesting the enteric nervous system might be the starting point for the whole process. Although accumulating and compelling evidence favors this theory, the remaining knowledge gaps are important points for future studies.

RESUMO O atual entendimento sobre a fisiopatologia da doença de Parkinson (DP) sugere um papel central do acúmulo de alfa-sinucleína na patogenia da DP Esta revisão crítica revisita marcos, teorias e controvérsias a respeito da origem e progressão da sinucleinopatia, apresentando uma atualização das principais evidências sugerindo que o sistema nervoso entérico seria o local inicial deste processo. Apesar das evidências a favor desta teoria serem crescentes e instigantes, as lacunas de conhecimento a este respeito são importantes pontos para estudos futuros.

Survival and Functional Outcomes after Hip Fracture among Nursing Home Residents

Following the implementation of a long-term care insurance system for the elderly in Korea, many nursing homes have been established and many more patients than ever before have been living at nursing homes. Despite the fact that this is a high-risk group vulnerable to hip fractures, no study has yet been conducted in Korea on hip fracture incidence rates and prognoses among patients residing at nursing homes. We recently studied 46 cases of hip fracture in nursing homes; more specifically, we investigated the most common conditions under which fractures occur, and examined the degree of recovery of ambulatory ability and the mortality within 1 yr. Among those who had survived after 1 yr, the number of non-functional ambulators increased from 8 hips before hip fracture to 19 hips at final post-fracture follow-up. These individuals showed poor recovery of ambulatory ability, and the number who died within one year was 11 (23.9%), a rate not significantly different from that among community-dwelling individuals. It was evident that hip-joint-fracture nursing home residents survived for similar periods of time as did those dwelling in the community, though under much more uncomfortable conditions. The main highlight of this report is that it is the first from Korea on nursing home residents' ambulatory recovery and one-year mortality after hip fracture. The authors believe that, beginning with the present study, the government should collect and evaluate the number of hips fractured at nursing facilities in order to formulate criteria that will help to enable all patients to select safer and better-quality nursing facilities for themselves or their family members.

Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs / Neuroinflamação na patofisiologia da doença de Parkinson e evidências terapêuticas de drogas antiinflamatórias

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.

A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum afetando aproximadamente 1,6% da população acima de 60 anos de idade. Os sinais motores cardinais são o resultado da degeneração progressiva de neurônios dopaminérgicos da substantia nigra pars compacta (SNpc), a qual está intimamente envolvida com o controle motor. Atualmente, não há cura para esta patologia e a causa da neurodegeneração permanece desconhecida. Contudo, muitos estudos sugerem o envolvimento da neuroinflamação na patofisiologia da DP bem como um efeito protetor de drogas antiinflamatórias tanto em modelos animais quanto em estudos epidemiológicos, embora haja relatos controversos. Nesta revisão, foram abordadas evidências de envolvimento do processo inflamatório e uma possível utilidade terapêutica de drogas antiinflamatórias na DP.

Atrofia múltiple de sistemas: presentación de un caso interesante / Multiple system atrophy: presenting an interesting case

Se presenta el caso de una mujer diestra de 58 años, con cuadro de Parkinson de diez años de evolución, trastorno de la marcha a petitpass, rigidez, hiperreflexia, atáxica, con dismetría, voz escandida, con alteración del mini mental test. Se define como la presencia de atrofia en la protuberancia, bulbo y cerebelo con hipo intensidad en núcleos de la base en Resonancia Magnética Nuclear, evidencia de atrofia cortical en Tomografía Cerebral, vejiga neurogénica, tratada por urólogo. Se discute la entidad Atrofia Múltiple de Sistemas (ASM) de las que existen varias formas, como la olivopontocerebelosa, la autonómica y la estriadonigral.

Studying neurodegenerative diseases in culture models

Neurodegenerative diseases are pathological conditions that have an insidious onset and chronic progression. Different models have been established to study these diseases in order to understand their underlying mechanisms and to investigate new therapeutic strategies. Although various in vivo models are currently in use, in vitro models might provide important insights about the pathogenesis of these disorders and represent an interesting approach for the screening of potential pharmacological agents. In the present review, we discuss various in vitro and ex vivo models of neurodegenerative disorders in mammalian cells and tissues.

Estudo da fadiga e qualidade de vida nos pacientes com doença de Parkinson / Study of fatigue and quality of life in patients with Parkinson' s disease

Objetivo - Analisar a ocorrência da fadiga na doença de Parkinson e sua relação na qualidade de vida desses indivíduos. A fadiga é um sintoma comum e debilitante em muitas doenças neurológicas. Estudos demonstram que vem sendo uma queixa frequente em pacientes com Parkinson. Métodos - Participaram da pesquisa 12 indivíduos de ambos os sexos, com doença de Parkinson, esses indivíduos não apresentaram problemas cognitivos que pudesse influenciar o resultado da pesquisa. A fadiga foi medida pela Escala de severidade da fadiga (FSS). Para análise da qualidade de vida foi aplicado o questionário PDQ-39 que é específico para avaliação da qualidade de vida na doença de Parkinson. Resultados - Dos sujeitos da amostra 50% apresentaram escore > 4 na escala FSS e foram definidos como portadores de fadiga, esta não apresentou significância com a idade dos sujeitos e nem com o tempo de lesão. Observou-se correlação muito significativa entre as dimensões fadiga e mobilidade e correlação significativa entre as dimensões fadiga e bem-estar emocional, estas dimensões analisadas abrangem aspectos motores da doença de Parkinson, e tais limitações físicas, contribuem para uma má qualidade de vida destes indivíduos. Conclusão - É possível observar o impacto substancialmente negativo da fadiga na qualidade de vida dos pacientes com doença de Parkinson, porém a escassez de estudos com esse tipo de análise limita a discussão desta associação, sendo que novas pesquisas precisam ser realizadas.

Objective - To analyze the occurrence of fatigue in Parkinson's disease and their relationship in the quality of life of individuals. Fatigue is a common and debilitating symptom in many neurological diseases. Studies show that has been a frequent complaint in patients with Parkinson's disease. Methods -We studied 12 individuals of both sexes with Parkinson's disease, these subjects had no cognitive problems that could influence the outcome of the research. Fatigue was measured by the Fatigue severity scale (FSS). For analysis the quality of life was applied the PDQ-39 that is specific for assessing the quality of life in Parkinson's disease. Results - From the studied individuals, 50% of the sample had of a score > 4 on a scale FSS and were defined as patients with fatigue did not show significance at the age of the subjects nor the time of injury. There was very significant correlation between the dimensions mobility and fatigue, and a significant correlation between the dimensions of fatigue and emotional well-being, those dimensions analyzed include motor aspects of Parkinson's disease, and such physical limitations, contribute to poor quality of life of individuals. Conclusion - It was possible to observe the substantial negative impact of fatigue on quality of life of patients with Parkinson's disease, but the scarcity of studies with this type of analysis limits the discussion of this association, and further research must be performed.

Different approaches, one target: understanding cellular mechanisms of Parkinson's and Alzheimer's diseases / Abordagens diferentes, um único objetivo: compreender os mecanismos celulares das doenças de Parkinson e de Alzheimer

Neurodegenerative disorders are undoubtedly an increasing problem in the health sciences, given the increase of life expectancy and occasional vicious life style. Despite the fact that the mechanisms of such diseases are far from being completely understood, a large number of studies that derive from both the basic science and clinical approaches have contributed substantial data in that direction. In this review, it is discussed several frontiers of basic research on Parkinson´s and Alzheimer´s diseases, in which research groups from three departments of the Institute of Biomedical Sciences of the University of São Paulo have been involved in a multidisciplinary effort. The main focus of the review involves the animal models that have been developed to study cellular and molecular aspects of those neurodegenerative diseases, including oxidative stress, insulin signaling and proteomic analyses, among others. We anticipate that this review will help the group determine future directions of joint research in the field and, more importantly, set the level of cooperation we plan to develop in collaboration with colleagues of the Nucleus for Applied Neuroscience Research that are mostly involved with clinical research in the same field.

Os transtornos neurodegenerativos são, sem dúvida, um problema crescente nas ciências da saúde, dado o aumento da expectativa de vida e de estilos de vida pouco saudáveis. Embora os mecanismos de tais doenças ainda estejam longe de ser esclarecidos, vários estudos que derivam tanto da ciência básica quanto de abordagens clínicas contribuíram nessa direção. Na presente revisão, são discutidas linhas de frente da pesquisa básica sobre as doenças de Parkinson e Alzheimer, em que grupos de pesquisas de três departamentos do Instituto de Ciências Biomédicas da Universidade de São Paulo estão envolvidos em um esforço multidisciplinar. O foco principal desta revisão envolve os modelos animais desenvolvidos para se estudar os aspectos celulares e moleculares daquelas doenças neurodegenerativas, incluindo o estresse oxidativo, a sinalização da insulina e as análises proteômicas, dentre outros. Antecipamos que esta revisão irá auxiliar o grupo a determinar as futuras direções da pesquisa conjunta nessa área e, o mais importante, estabelecer o nível de cooperação que planejamos desenvolver juntamente com colegas do Núcleo de Apoio à Pesquisa em Neurociência Aplicada que estão envolvidos com pesquisa clínica na mesma área.

La regulación del transportador de colina de alta afinidad dependiente de AMPc/PKA no es mediada por dopamina en neuronas de retina / cAMP/PKA - dependent regulation of the high affinity choline transporter is not mediated by dopamine in retinal neurons

La actividad del transportador de colina de alta afinidad (HAChT) es considerado el paso limitante en la síntesis de acetilcolina (ACh) en el terminal colinérgico. Estudios recientes muestran que el HAChT contiene residuos de serina y treonina consensuales para la fosforilación por proteína kinasa A (PKA). Usando neuronas de retina de embrión de pollo se evaluó el efecto del segundo mensajero AMPc sobre la actividad del HAChT. El aumento de los niveles intracelulares de AMPc a través de la inhibición de la fosfodiesterasa, activación de la adenilato ciclasa o usando un análogo de AMPc resistente a la fosfodiesterasa disminuyó la actividad del HAChT entre 29 y 69%. Por otra parte, la activación de receptores de dopamina tipo-D1 aumenta los niveles de AMPc intracelular y activa PKA, sin embargo, el tratamiento con dopamina o con antagonistas de los receptores dopaminergicos D1 o D2 no induce cambios en la actividad del transportador

The high affinity choline transporter (HAChT) activity is considered to be the rate-limiting step in acetylcholine (ACh) synthesis in the cholinergic terminal. Recent studies show that HAChT contains consensus serine and threonine residues for protein kinase A (PKA) phosphorylation. Using chick retinal neurons evaluated the effects of the second messenger cAMP on the HAChT activity. The increase of the intracellular cAMP levels through phosphodiesterase inhibition, adenilatecyclase activation or using a phosphodiesterase-resistant cAMP analog decreased HAChT activity between 29 and 69%. Moreover, the activation of dopamine D1-type receptors increase the intracellular cAMP levels and activates PKA, however, the treatment with dopamine D1 or D2 receptor antagonists does not induce changes on transporter activity

Diagnóstico precoz de la enfermedad de Parkinson / Early diagnosis in Parkinson's disease

La enfermedad de Parkinson (EP) se caracteriza por la presencia de síntomas motores que aparecen cuando ha ocurrido una extensa pérdida de neuronas dopaminérgicas a nivel de la sustancia negra. En las últimas décadas diversos hallazgos mostraron que el inicio del proceso degenerativo tiene lugar varios años antes de la aparición de los síntomas, involucrando numerosos sistemas de neurotransmisión. Diversas manifestaciones clínicas como disfunción olfatoria, trastorno conductual del sueño REM, depresión y constipación, entre otras, preceden a la aparición de los síntomas motores. Además, las neuroimágenes han permitido reconocer algunos de los sujetos en riesgo de presentar EP a partir de síntomas tempranos o en portadores de mutaciones genéticas asociadas con la EP. En este artículo revisamos la información disponible sobre el diagnóstico en la etapa temprana de la EP, antes de los síntomas motores y cómo esta estrategia puede ser de utilidad en el mejor tratamiento de esta población de pacientes.

Neuroprotective effects of deprenyl and certain natural products against paraquat-induced behavioral and neurochemical changes in rats

Paraquat [PQ] belongs to a class of agricultural chemicals known to impact the dopaminergic system adversely causing severe neurotoxicity. PQ was suggested to contribute in the pathogenesis of many neurological disorders including Parkinson's disease. So, the present study aimed to examine the toxic alterations in brain tissue, following sub-chronic treatment with PQ [20 mg/kg, i.p., once weekly for 6 weeks].Three different types of experiments were carried out including behavioral, neurochemical and histopathological ones. Alterations of motor behavioral patterns were examined by testing the locomotor activity using the open field test and the movement coordination using the rotarod apparatus. Changes in brain dopamine [DA] and norepinephrine [NE] contents as well as histopathological examination of brain tissues were accomplished. The possible protective potentials of deprenyl [10 mg/kg; i.p.], quercetin [50 mg/kg; p.o.], green tea extract [1 mg/kg; p.o.] or malt extract [625 mg/kg; p.o.] against sub-chronic PQ-induced neurotoxicity in rats were examined. Results showed that PQ significantly reduced locomotive and motor behaviors. It also provoked remarkable brain damage noted by significant decreases in brain DA as well as NE contents. Furthermore, histopathological examination of PQ-treated brain sections revealed localized focal necrosis and severe loss of neurons. Daily treatment with deprenyl, quercetin and extracts of green tea or malt for 6 weeks significantly ameliorated most of the behavioral, neurochemical and histopathological changes induced by PQ; effects of malt extract being more pronounced. The present results suggest that sub-chronic PQ administration triggers processes characteristic of early stages of dopaminergic neuron degeneration and activates compensatory mechanisms involving both the dopaminergic and noradrenergic transmissions. Considering the present behavioral studies, neurochemical analysis and histopathological observations, one can conclude that the used agents could be of therapeutic potentials in protection against PQ- induced neurotoxicity

Mitocôndria e doença de Parkison: contibuições da genética no conhecimento do processo / Mitochondria and Parkinson disease: genetic contibuitions to understanding the pathogenic process

A doença de Parkinson é a segunda doença neurodegenerativa mais comum.A disfunção mitocondrial exerce um papel importante na patogênese desta enfermidade. Os estudos das formas monogênicas de parkinsonismo contribuíram de forma significativa para uma melhor compreensão deste processo. Revisamos como estes genes se adequam no entendimento do papel da disfunção mitocondrial na doença de Parkinson.

Parkinsonism and tremor disorders: a clinical approach

Differentiation of idiopathic Parkinson's disease from other causes of Parkinsonism, such as Multiple System Atrophy, Progressive Supranuclar Palsy and Vascular Parkinsonism can be difficult. Clinicopathological studies suggest that the clinical diagnosis of idiopathic Parkinson's disease is 76% reliable. Also, clinical differentiation of tremor prominent Parkinsonism from Essential Tremor or Drug induced Parkinsonism may be problematic, especially in the early stages of the disease. Since these disorders are obviously different in clinical progress, it is important for the clinician to address the patient's and family's concerns about prognosis from a firm diagnostic footing. In this article the clinical features of the common and important causes of Parkinsonism and tremor disorders are reviewed and a practical approach is suggested

Neuroprotective effect of BDNF in young and aged 6-OHDA treated rat model of Parkinson disease.

Brain derived neurotrophic factor (BDNF) has been shown to exert trophic effects on dopaminergic neurons against 6-hydroxydopamine (6-OHDA) in young rat. Since the degeneration of substantia nigra dopaminergic neurons that occurs in Parkinson's disease is more often than not confined to elderly individuals, it is of interest to determine whether the effects of BDNF against 6 hydroxydopamine (6-OHDA) in young rats can be extended to aged animals. 6-hydroxydopamine was stereotaxically injected into the striatum of young (3-months) and aged (24-months) rats, which were treated two hours earlier with BDNF. 6-OHDA results in almost complete destruction of substantia nigra pars compacta dopaminergic neurons. BDNF injection significantly changed apomorphine induced rotations from 132 +/- 15 to 181 +/- 10, staircase test from 73 +/- 2% to 61 +/- 3%, initiation time from 7 +/- 2 to 12 +/- 1 sec, and disengage time from 80 +/- 7 to 90 +/- 5 sec in young and aged animals, respectively. It is concluded that BDNF causes the limited behavior recovery of striatal DA systems from 6-OHDA toxicity in aged animals.

State of the art: deep brain stimulation in Parkinson's disease.

Surgical therapy for Parkinson's disease has a long history beginning in the 1930s with empirical exploration of different brain targets, such as resection of the primary motor cortex or extirpation of the caudate. Recently, there has been a renaissance of functional neurosurgery for the treatment of advanced Parkinson's disease, particularly deep brain stimulation (DBS). To date, DBS of the globus pallidus interna and subthalamic nucleus has been reported to relieve motor symptoms and levodopa-induced dyskinesia in patients with advanced Parkinson's disease. DBS also has different advantages over pallidotomy and subthalamotomy, including reversibility, decreased risk of reoperation and decreased morbidity. In addition to well-experienced neurologists and neurosurgeons, a multidisciplinary team approach is fundamental and critical to ensure success in the DBS procedure in individual patients. With the advances in neuroimaging, neurophysiology and localization techniques, it is increasingly likely that there will be more surgical targets in the future that can also improve cardinal features of Parkinson's disease, or even nonmotor manifestations of this condition.

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1beta, TNF-alpha, IL-6), NO, PGE