The Gut Brain-Axis in Neurological Diseases

Abstract Recent evidence suggests that dysfunction of the gut-brain axis may be an important factor contributing to many diseases of the nervous system. Increased gut permeability associated with chronic gastrointestinal dysfunction, as well as changes in the composition of the gut microbiota could contribute to exposure of the enteric and central nervous system to pathogens and its metabolites, including endotoxins and pro-inflammatory cytokines. As a consequence, dysfunction of the host's immune system could contribute to an abnormal immunological response leading to auto-immune conditions, such as multiple sclerosis. So far, gut dysbiosis has been reported in association with Parkinson's disease, Alzheimer's disease, multiple sclerosis, neurodevelopmental and neuropsychiatric conditions, and cerebrovascular disease. These findings suggest that the possibility of targeting the gut microbiota could become a future therapeutic option to treat these conditions. However, before this knowledge can be useful in the clinical setting, more data is needed to establish clear causal relationships between dysfunction of the gut-brain axis and neurological diseases.

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.

Parasomnias: an overview.

Parasomnias are abnormal experiences or behaviours that occur during sleep and can be subdivided into disorders of arousal, disorders of rapid eye movement (REM) sleep or other parasomnias. Diagnosis rests on a thorough clinical evaluation with supporting data from a full polysomnography with time synchronized video. While the prognosis for arousal disorders is generally excellent, the diagnosis of REM behaviour disorder (RBD) is more ominous and associated with neurodegenerative disorders, and as such, requires routine neurological surveillance. The cornerstone of treatment for all parasomnias is adequate patient and bed partner education. Data supporting pharmacologic therapy are limited but clonazapam for RBD has been reported to be effective in up to 89 per cent of patients.

Molecular and pathological basis of aceruloplasminemia

Aceruloplasminemia is an autosomal recessive neurodegenerative disease characterized by iron accumulation in the brain as well as visceral organs. It is a loss-of-function disorder caused by mutations in the ceruloplasmin gene. Clinically, this disease consists of the triad of adult-onset neurological disease, retinal degeneration and diabetes mellitus. Massive iron accumulation and extensive loss of neurons are observed in the basal ganglia. The elevated iron concentration is associated with increased lipid peroxidation in the brains of aceruloplasminemia patients. Enlarged or deformed astrocytes and spheroid-like globular structures are characteristic neuropathological findings in aceruloplasminemia. Moreover, deformed astrocytes and globular structures react positively to anti-4-hydroxynonenal antibody, suggesting that increased oxidative stress is involved in neuronal cell death in aceruloplasminemia brain. More than 30 aceruloplasminemia-causing mutations in the ceruloplasmin gene have been identified. We examined the biosynthesis of two missense ceruloplasmin proteins that result from a Japanese P177R mutation and a Dutch G631R mutation, using Chinese hamster ovary cell expression system. The P177R mutant protein is retained in the endoplasmic reticulum. The G631R mutant protein, predicted to alter the interactions at a single type I copper-binding site, prevented incorporation of copper into apoceruloplasmin and resulted in the synthesis and secretion only of apoceruloplasmin. Molecular analysis of missense mutations showed different structure-function relationships in ceruloplasmin protein. The investigation of mutant ceruloplasmin reveals new insights into molecular pathogenesis of aceruloplasminemia as well as biosynthesis, trafficking, and function of ceruloplasmin.

Hiperhomocisteinemia: um fator de risco para as doenças do século XX / Hyperhomocysteinemia: a risk factor for diseases of the twentieth century

Introdução: A homocisteína é um aminoácido sulfurado derivado da metionina que está associado á gênese de várias doenças não transmissíveis. Sua concentração plasmática é resultado de fatores genéticos, hormonais e nutricionais, como o estado nutricional das vitaminas ácido fólico, cobalamina e piridxina. A hiperhomocisteinemia, mesmo que leve, é considerada fator de risco independente para doença cardiovascular, estando associada a eventos tromboembólicos, doença arterosclerótica e hipertensão arterial. Além disso, também está relacionada à resistência insulínica e, consequentemente, á síndrome metabólica. Objetivo: Discutir a possível associação da hiperhomocisteinemia com a ocorrência de doenças e agravos não transmissíveis, através de ampla revisão bibliográfica. Método: realizou-se levantamento bibliográfico dos últimos seis anos, consultando as bases de dados do Medline, Sielo, Lilacs, sendo selecionados artigos mais relevantes relacionados com o objetivo desta revisão. Conclusões: Vários estudos sugerem a possível associação da hiperhomocisteinemia com doenças de grande impacto social, como as cardiovasculares, o câncer, as doenças do sistema digestório, a insuficiência renal e as doenças neurodegenerativas. Esses resultados demonstram a importância da realização de pesquisas científicas nesta área a fim de estudar essa possível associação. portanto, o tratamento da hiperhomocisteinemia constitui-se numa estratégia eficaz para a prevenção de tais doenças. Esse tratamento deve se basear, principalmente, no incremento do estado nutricional do folato, o que se tornou mais acessível no Brasil após o enriquecimento de alguns alimentos com essa vitamina.

Introduction: Homocysteine is a sulfur-containing amino acid derived from methionine that is associated to the genesis of several noncommunicable diseases. Its plasma concentration is the result of genetic, hormonal and nutritional factors, such as the nutritional status of the vitamins folic acid, cobalamin and piridxina. Hyperhomocysteinemia, even slight, is considered an independent risk factor for cardiovascular disease and is associated with thromboembolic events, atherosclerotic disease and hypertension. It also is related to insulin resistance and hence the metabolic syndrome. Objective: To discuss the possible association of hyperhomocysteinemia and the occurrence of non-communicable diseases and injuries, through extensive literature review. Method: literature review took place over the last six years, consulting the databases of Medline, Siel, Lilacs, being selected most relevant articles related to the purpose of this review. Conclusions: Several studies suggest a possible association of hyperhomocysteinemia with diseases of major social impact such as cardiovascular disease, cancer, digestive system diseases, renal failure and neurodegenerative diseases. These results demonstrate the importance of conducting scientific research in this area in order to study this possible association. therefore, the treatment of hyperhomocysteinemia constitutes a successful strategy for the prevention of such diseases. This treatment should be based mainly in increasing the nutritional status of folate, which became more accessible in Brazil after the enrichment of foods with this vitamin.

Aspectos etiopatogênicos da Doença de Huntington / Etiopathogenic aspects of Huntington's disease

A doença de Huntington (DH) é um distúrbio hereditário autossômico dominante, que está relacionado à expansão das repetições de CAG (citosina-adenina-guanina) no braço curto do cromossomo 4, o que leva à formação de uma proteína mutante associada, principalmente, à destruição neuronal do estriado. Manifesta-se por transtornos motores, cognitivos e neuropsicológicos, evoluindo progressivamente para estado demencial grave. A patogênese da doença ainda apresenta pontos obscuros. No entanto, recentes investigações têm possibilitado maior entendimento de sua origem e evolução, assim como de outras doenças neurodegenerativas

Huntington's disease is a hereditary autosomal dominant disorder which occurs due to the expansion of the repetitions CAG on the short arm of chromosome 4, which leads to the formation of a mutant protein itself associated principally to the destruction of neuronal of the striated tissue. It manifests through motor, cognitive and neuropsychological disorders where it evolves progressively to a serious demential state. The pathogenesis of this disease still presents obscure points although recent investigations made it possible to understand it better in its origin and evolution, the same as with other neurodegenerative diseases

Patología médica ocasionada por repetidos de trinucleótidos / Medical pathology occasioned by trinucleotide repeat

Se han descrito diez enfermedades genéticas en donde la alteración es la expansión de repeticiones de trinucleótidos. Existen cuatro tipos de secuencias trinucleotídicas involucradas en expansiones. El tipo, posición en un gen y número de copias en los individuos afectados, varía según la enfermedad. Algunas de estas repeticiones expandibles están relacionadas con sitios frágiles en los cromosomas y cuando se encuentran expandidas existen 2000 o más copias de la secuencia. Otro tipo de secuencias repetidas se localiza en regiones codificadoras de genes relacionados con problemas neurodegenerativos, como el mal de Huntington, atrofia muscular espinobulbar o ataxia espinocerebral tipo 1, en donde presentan expansiones cortas de 60 a 90 copias del trinucleótido en el gen. La expansión continua de repetidos en estos padecimientos puede explicar la anticipación genetíca que caracteriza a estas enfermedades y existe una correlación entre la gravedad de la enfermedad y el número de repetidos. Recientemente se ha demostrado este tipo de expansión en secuencias mayores del tipo minisatélites: En un caso, está relacionada con la epilepsia tipo 1 y en la otra al sitio frágil 16B sensible a Distancia. Esta forma de herencia es importante por su relación con algunas de las enfermedades degenerativas más comunes en los humanos