RESUMO
AIMS: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons. METHODS: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology. RESULTS: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD. CONCLUSION: These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.
Assuntos
Doenças Inflamatórias Intestinais , Doença de Parkinson , Humanos , Ratos , Animais , alfa-Sinucleína/metabolismo , Doença de Parkinson/patologia , Encéfalo/patologia , Inflamação/patologia , Neurônios Dopaminérgicos/metabolismo , Doenças Inflamatórias Intestinais/patologiaRESUMO
Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease.
Assuntos
Anti-Inflamatórios/toxicidade , Corpo Estriado/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Metformina/toxicidade , Transtornos Parkinsonianos , Substância Negra/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Técnicas de Cultura de Células , Linhagem Celular , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Imuno-Histoquímica , Masculino , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Substância Negra/metabolismo , Substância Negra/patologiaRESUMO
Neurodegenerative diseases are characterized by a progressive deterioration of brain function, with a consequent significant decline in the quality of life of patients and their families. Due to the concurrent increase in life expectancy, the incidence of these diseases has been increasing over the last years and thus there is a growing interest in finding potential risk factors. This review focuses on the correlation between peripheral inflammatory diseases and neurodegeneration, in particular on the relationship between gastrointestinal disorders and Parkinson's disease, especially through the so called gut-brain axis.
Assuntos
Gastroenteropatias/fisiopatologia , Inflamação/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/fisiopatologia , Doença de Alzheimer/fisiopatologia , Animais , Doença Crônica , Suplementos Nutricionais , Encefalite/fisiopatologia , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Microglia/patologia , Microglia/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
This review is aimed to highlight the importance of stress and glucocorticoids (GCs) in modulating the inflammatory response of brain microglia and hence its potential involvement in Parkinson's disease (PD). The role of inflammation in PD has been reviewed extensively in the literature and it is supposed to play a key role in the course of the disease. Historically, GCs have been strongly associated as anti-inflammatory hormones. However, accumulating evidence from the peripheral and central nervous system have clearly revealed that, under specific conditions, GCs may promote brain inflammation including pro-inflammatory activation of microglia. We have summarized relevant data linking PD, neuroinflamamation and chronic stress. The timing and duration of stress response may be critical for delineating an immune response in the brain thus probably explain the dual role of GCs and/or chronic stress in different animal models of PD.