Publicação
Human phenolic metabolites as modulators of neuroinflammation
| Resumo: | Neurodegenerative diseases are characterised by progressive degeneration and loss of neurons. With the aging of the world population, their incidence is predicted to increase. As these diseases are incurable and the only existing therapies merely attenuate the symptoms, a great interest in preventing them arises. Neuroinflammation is hallmark common to many neurodegenerative diseases. It is mediated by microglia, innate immune cells resident in the central nervous system. Their main function in the healthy brain is surveillance, and they also participate in neurogenesis during development. When damage occurs, these cells become transiently activated and gain a pro-inflammatory phenotype, which is beneficial and allows them to protect the brain. However, in neurodegenerative diseases this activation becomes chronic, and microglia becomes deleterious and induces neuron loss. Phenolic compounds are phytochemicals easily obtained through a healthy diet that have been demonstrated to have anti-inflammatory properties. However, when obtained through diet, they are more likely to reach the brain as modified metabolites than as parent compounds. Importantly, to act over microglia, they must cross the blood-brain barrier. Following an intervention study where colonic phenolic metabolites were identified in circulation after consumption of a berry purée, the compounds were tested for the ability to cross the blood-brain barrier. Not only they were found to be transported across it, the same study discovered that pyrogallol-sulfate, one of the metabolites that reached the highest concentrations in circulation, could attenuate neuroinflammation in microglia. Most neuroinflammation studies use lipopolysaccharide (LPS) as a stimulus. However, its presence in the brain in vivo is unlikely. This work created a new inflammation model in murine microglia using tumour necrosis factor (TNF)α and interferon (IFN)γ, two cytokines more likely to be found in the brain and known to be increased in neurodegenerative diseases. Different concentrations were tested, and compared with the commonly used LPS insult. Several pro- and anti-inflammatory factors were evaluated to characterise cell response. After establishing the model, this work used it to assess the ability of phenolic compounds to attenuate neuroinflammation. The compounds used were catechol-sulfate and pyrogallol-sulfate, already tested in a model using LPS, and phloroglucinol-sulfate, resorcinol-sulfate and pyrogallol-glucoronide, which are chemically similar to pyrogallol. They showed different effects over different markers suggesting a pleiotropic action. Pyrogallol sulfate also showed potential to attenuate inflammation in this model. |
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| Autores principais: | Bento, Maria Inês Varela Costa de Vasconcelos |
| Assunto: | Metabolitos fenólicos Neuroinflamação Microglia TNFα IFNγ Teses de mestrado - 2018 |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Neurodegenerative diseases are characterised by progressive degeneration and loss of neurons. With the aging of the world population, their incidence is predicted to increase. As these diseases are incurable and the only existing therapies merely attenuate the symptoms, a great interest in preventing them arises. Neuroinflammation is hallmark common to many neurodegenerative diseases. It is mediated by microglia, innate immune cells resident in the central nervous system. Their main function in the healthy brain is surveillance, and they also participate in neurogenesis during development. When damage occurs, these cells become transiently activated and gain a pro-inflammatory phenotype, which is beneficial and allows them to protect the brain. However, in neurodegenerative diseases this activation becomes chronic, and microglia becomes deleterious and induces neuron loss. Phenolic compounds are phytochemicals easily obtained through a healthy diet that have been demonstrated to have anti-inflammatory properties. However, when obtained through diet, they are more likely to reach the brain as modified metabolites than as parent compounds. Importantly, to act over microglia, they must cross the blood-brain barrier. Following an intervention study where colonic phenolic metabolites were identified in circulation after consumption of a berry purée, the compounds were tested for the ability to cross the blood-brain barrier. Not only they were found to be transported across it, the same study discovered that pyrogallol-sulfate, one of the metabolites that reached the highest concentrations in circulation, could attenuate neuroinflammation in microglia. Most neuroinflammation studies use lipopolysaccharide (LPS) as a stimulus. However, its presence in the brain in vivo is unlikely. This work created a new inflammation model in murine microglia using tumour necrosis factor (TNF)α and interferon (IFN)γ, two cytokines more likely to be found in the brain and known to be increased in neurodegenerative diseases. Different concentrations were tested, and compared with the commonly used LPS insult. Several pro- and anti-inflammatory factors were evaluated to characterise cell response. After establishing the model, this work used it to assess the ability of phenolic compounds to attenuate neuroinflammation. The compounds used were catechol-sulfate and pyrogallol-sulfate, already tested in a model using LPS, and phloroglucinol-sulfate, resorcinol-sulfate and pyrogallol-glucoronide, which are chemically similar to pyrogallol. They showed different effects over different markers suggesting a pleiotropic action. Pyrogallol sulfate also showed potential to attenuate inflammation in this model. |
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