Caracterização do perfil metabólico do roedor Proechimys sp. submetido a um modelo de doença de Parkinson induzida pela 6-hidroxidopamina
Data
2024-03-08
Autores
Cardillo, Giancarlo de Mattos 
Orientadores
Scorza, Fulvio Alexandre
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A doença de Parkinson é uma das mais frequentes doenças neurodegenerativas em seres humanos. Ela é caracterizada por tremores, acinesia, rigidez muscular e perda de reflexo postural, causados pela perda de neurônios dopaminérgicos na substantia nigra, processo que está intimamente relacionado ao aumento de estresse oxidativo na região. O Proechimys sp. é um roedor amazônico de grande potencial no campo da neurociência, apresentando resistência a tratamentos epileptogênicos, citoarquitetura hipocampal diferenciada e resistência à indução de morte dopaminérgica induzida pela 6-hidroxidopamina (6-OHDA). Métodos que exploram de forma ampla o perfil fisiológico ou em um contexto patológico são essenciais para a caracterização do modelo, bem como encontrar possíveis alvos terapêuticos. Entre esses métodos destaca-se a metabolômica, que fornece informações do estado de funcionamento metabólico dos sistemas biológicos. Objetivo: O objetivo do presente estudo foi determinar o perfil metabólico do roedor Proechimys sp. frente ao modelo de morte dopaminérgica induzido pela 6-OHDA. Métodos: 6-OHDA foi administrada intracerebralmente no estriado de roedores Proechimys sp. para acessar o perfil de concentração de metabólitos no estriado, córtex frontal, hipocampo e cerebelo 40 dias após a administração da droga, sendo o grupo controle composto por roedores que receberam soro fisiológico intracerebralmente, pela mesma metodologia. Resultados: A análise metabolômica apontou significantes alterações nas concentrações de metabólitos no estriado e córtex frontal nos animais que receberam 6-OHDA, com destaque para cisteína, glicose-6-fosfato, mio-inositol e glicerol-3-fosfato mostrando impactos em vias metabólicas associadas principalmente ao metabolismo da glicose e resposta à geração de espécies reativas de oxigênio. Conclusões: Nossos dados apontam um quadro metabólico alterado nos animais que receberam 6-OHDA, sugerindo um aumento no nível de estresse oxidativo e alterações no metabolismo fisiológico associado à glicose, semelhantes aos observados em pacientes com doença de Parkinson, suplantando a aparente resistência aguda indicada previamente no Proechimys sp. As vias impactadas, além de corroborarem a literatura, indicam potenciais alvos terapêuticos a serem explorados e a relevância do Proechimys sp. como modelo animal para esses estudos.
Introduction: Parkinson's disease is one of the most common neurodegenerative diseases in humans. It is characterized by tremors, akinesia, muscle rigidity and loss of postural reflex, caused by the loss of dopaminergic neurons in the substantia nigra, a process that is closely related to the increase in oxidative stress in the region. Proechimys sp. is an Amazonian rodent with great potential in the field of neuroscience, presenting resistance to epileptogenic treatments, differentiated hippocampal cytoarchitecture and resistance to the induction of dopaminergic death induced by 6-hydroxipamine (6-OHDA). Methods that broadly explore the physiological profile or in a pathological context are essential for characterizing the model, as well as finding possible therapeutic targets. Among these methods, metabolomics stands out, which provides information on the metabolic functioning status of biological systems. Objective: The objective of the present study was to determine the metabolic profile of the rodent Proechimys sp. against the model of dopaminergic death induced by 6-OHDA. Methods: 6-OHDA was administered intracerebrally into the striatum of Proechimys sp. rodents to access the metabolite concentration profile in the striatum, frontal cortex, hippocampus, and cerebellum 40 days after drug administration, with the control group consisting of rodents that received saline solution intracerebrally, through the same methodology. Results: Metabolomic analysis showed significant changes in the concentrations of metabolites in the striatum and frontal cortex in animals challenged with 6-OHDA, with emphasis on cysteine, glucose-6-phosphate, myo-inositol and glycerol-3-phosphate, showing impacts on metabolic pathways associated mainly with glucose metabolism and response to the generation of reactive oxygen species. Conclusions: Our data point to an altered metabolic picture in animals that received 6-OHDA, suggesting an increase in the level of oxidative stress and changes in physiological metabolism associated with glucose, similar to those observed in patients with Parkinson's disease, overcoming the apparent acute resistance indicated previously in Proechimys sp. The impacted pathways, in addition to corroborating the literature, indicate potential therapeutic targets to be explored and the relevance of Proechimys sp. as an animal model for these studies.
Introduction: Parkinson's disease is one of the most common neurodegenerative diseases in humans. It is characterized by tremors, akinesia, muscle rigidity and loss of postural reflex, caused by the loss of dopaminergic neurons in the substantia nigra, a process that is closely related to the increase in oxidative stress in the region. Proechimys sp. is an Amazonian rodent with great potential in the field of neuroscience, presenting resistance to epileptogenic treatments, differentiated hippocampal cytoarchitecture and resistance to the induction of dopaminergic death induced by 6-hydroxipamine (6-OHDA). Methods that broadly explore the physiological profile or in a pathological context are essential for characterizing the model, as well as finding possible therapeutic targets. Among these methods, metabolomics stands out, which provides information on the metabolic functioning status of biological systems. Objective: The objective of the present study was to determine the metabolic profile of the rodent Proechimys sp. against the model of dopaminergic death induced by 6-OHDA. Methods: 6-OHDA was administered intracerebrally into the striatum of Proechimys sp. rodents to access the metabolite concentration profile in the striatum, frontal cortex, hippocampus, and cerebellum 40 days after drug administration, with the control group consisting of rodents that received saline solution intracerebrally, through the same methodology. Results: Metabolomic analysis showed significant changes in the concentrations of metabolites in the striatum and frontal cortex in animals challenged with 6-OHDA, with emphasis on cysteine, glucose-6-phosphate, myo-inositol and glycerol-3-phosphate, showing impacts on metabolic pathways associated mainly with glucose metabolism and response to the generation of reactive oxygen species. Conclusions: Our data point to an altered metabolic picture in animals that received 6-OHDA, suggesting an increase in the level of oxidative stress and changes in physiological metabolism associated with glucose, similar to those observed in patients with Parkinson's disease, overcoming the apparent acute resistance indicated previously in Proechimys sp. The impacted pathways, in addition to corroborating the literature, indicate potential therapeutic targets to be explored and the relevance of Proechimys sp. as an animal model for these studies.
Descrição
Citação
CARDILLO, Giancarlo de Mattos. Caracterização do perfil metabólico do roedor Proechimys sp. submetido a um modelo de doença de Parkinson induzida pela 6-hidroxidopamina. 2024. 82 f. Tese (Doutorado em Neurologia - Neurociências) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2024.