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Inibidores das desacetilases das histonas no tratamento de doenças com defeitos de memória
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As desacetilases das histonas (HDACs) têm um papel importante na homeostasia dos níveis de acetilação das histonas e algumas proteínas não-histonas, regulando assim processos celulares fundamentais como a transcrição. Este mecanismo epigenético, tal como outras modificações pós-tradução das histonas e a metilação do DNA, têm demonstrado ser importantes nos processos de aprendizagem e memória. De facto, existem cada vez mais evidências de que alterações na estrutura da cromatina estão envolvidas na etiologia de doenças neurodegenerativas e neuropsiquiátricas. Desse modo, os inibidores das HDACs (HDACi) têm exibido propriedades neuroprotectoras e neuroregenerativas em vários modelos de doenças como Alzheimer, Parkinson, Huntington, entre outras. De facto, as HDACs parecem ser um bom alvo terapêutico em doenças associadas a defeitos cognitivos, tendo já sido demonstrado que os HDACi conseguem reverter muitos destes defeitos através da indução da expressão de genes implicados nos processos de aprendizagem e memória, entre outros. O grande desafio continua a ser no entanto o desenvolvimento de um potente e eficaz inibidor das HDACs com excelente permeabilidade da barreira hemato-encefálica, com menos citotoxicidade e menos efeitos adversos.
Histone deacetylases (HDACs) play an important role in homeostasis of acetylation levels of histones and other non-histone proteins, and thus regulating fundamental cellular activities such as transcription. These epigenetic mechanisms, as other posttranslational modifications of histones and DNA methylation, have shown to be important in learning and memory processes. In fact, there is accumulating evidence that altered chromatin plasticity is involved in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Therefore, HDAC inhibitors (HDACi) exhibit neuroprotective and neuroregenerative properties in animal models of various brain diseases, like Alzheimer’s, Parkinson’s, Huntington’s, and many others. In fact, HDACs seem to be a good therapeutic target in diseases associated with cognitive deficits, and it has been demonstrated that HDACi can reverse much of these deficits through the induction of gene expression related to learning and memory processes, and others. However, the great challenge is still the development of a potent and efficient HDAC inhibitor with an excellent permeability of the hematoencephalic barrier, with less citotoxicity and less side effects.
Histone deacetylases (HDACs) play an important role in homeostasis of acetylation levels of histones and other non-histone proteins, and thus regulating fundamental cellular activities such as transcription. These epigenetic mechanisms, as other posttranslational modifications of histones and DNA methylation, have shown to be important in learning and memory processes. In fact, there is accumulating evidence that altered chromatin plasticity is involved in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Therefore, HDAC inhibitors (HDACi) exhibit neuroprotective and neuroregenerative properties in animal models of various brain diseases, like Alzheimer’s, Parkinson’s, Huntington’s, and many others. In fact, HDACs seem to be a good therapeutic target in diseases associated with cognitive deficits, and it has been demonstrated that HDACi can reverse much of these deficits through the induction of gene expression related to learning and memory processes, and others. However, the great challenge is still the development of a potent and efficient HDAC inhibitor with an excellent permeability of the hematoencephalic barrier, with less citotoxicity and less side effects.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2013
Palavras-chave
Epigenética HDACs HDACis Neurodegeneração Memória Mestrado Integrado - 2013