Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais

Detalhes bibliográficos
Autor(a) principal: Wiprich, Melissa Talita
Data de Publicação: 2019
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da PUC_RS
Texto Completo: http://tede2.pucrs.br/tede2/handle/tede/8724
Resumo: Huntington’s disease (HD) is a neurodegenerative genetic inheritance condition caused by an abnormal expansion of the CAG trinucleotide resulting in a mutation of the huntingtin protein. It is characterized by a triad of symptoms with progressive alterations of motor, cognitive and psychiatric functions. The first symptoms usually appear in the adult phase, but they can also appear in the juvenile age, around the 20 years old, being denominated juvenile HD. The disease becomes fatal 15 to 20 years after the onset of the first symptoms. In addition, the age of onset and intensity of symptoms are related to the number of CAG repeats, i.e. the more CAG repeats, the earlier the pathology develops and the greater the intensity of symptoms. The main neuropathological characteristic of HD is the remarkable neurodegeneration of the midline striatal neurons, altering different neurotransmitter systems, such as GABAergic, glutamatergic, dopaminergic, and adenosinergic. Currently, animal models of HD usually use rodents and non-human primates and are classified into genetic and pharmacological models. Among the pharmacological agents, the most commonly tested is the mitochondrial toxin model with the use of 3-nitropropionic acid (3-NPA), that inhibits the mitochondrial complex II-III and is able to reproduce the motor and biochemical alterations occurred in HD. In this context, zebrafish has become an excellent animal model for the study and development of neurodegenerative disease models. In this study, we performed a behavior screening in larval and adult zebrafish to establish the 3-NPA induced HD model. In the larval stage, the treatment consisted of exposure to 3-NPA at concentrations of 0.01, 0.05, 0.1, 0.2 and 0.5 mM for 7 days post-fertilization (dpf). From the 7th dpf to 14th dpf the animals remained only in the water. For the treatment of adult animals, the doses used were 10, 20, and 60 mg/kg and saline for the control group. The treatment consisted of 7 intraperitoneal injections performed every 96 hours.The locomotor and anxiety behavior was assessed 24 hours after each injection and the social interaction, aggression and memory at the end of the 29 days of the treatment. In the larval stage, the exposure to 3-NPA at concentrations of 0.1, 0.2 and 0.5 mM increased the heart rate at 2 and 5 dpf, caused a morphological alteration at the concentration of 0.05 mM and did not alter the locomotor behavior at the ages of 7, 10 and 14 dpf. In the adult stage, the exposure to 3-NPA in the doses at 10, 20, and 60 mg/kg induced a decrease in locomotor activity whereas it had no effect on anxiety and social interaction of the animals. However, the dose of 60 mg/kg caused a decrease in aggressive behavior and a memory impairment in the inhibitory avoidance task. These data suggest that zebrafish in the larval stage is a viable model for studying the characteristics of the pre-manifestation phase of HD and, in the adult stage, we identified through the long-term treatment with 3-NPA a new animal model to study the phenotypic characteristics of the late stage of HD.
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spelling Bonan, Carla Denisehttp://lattes.cnpq.br/8058052532279136http://lattes.cnpq.br/3816230343785348Wiprich, Melissa Talita2019-06-17T13:37:46Z2019-03-20http://tede2.pucrs.br/tede2/handle/tede/8724Huntington’s disease (HD) is a neurodegenerative genetic inheritance condition caused by an abnormal expansion of the CAG trinucleotide resulting in a mutation of the huntingtin protein. It is characterized by a triad of symptoms with progressive alterations of motor, cognitive and psychiatric functions. The first symptoms usually appear in the adult phase, but they can also appear in the juvenile age, around the 20 years old, being denominated juvenile HD. The disease becomes fatal 15 to 20 years after the onset of the first symptoms. In addition, the age of onset and intensity of symptoms are related to the number of CAG repeats, i.e. the more CAG repeats, the earlier the pathology develops and the greater the intensity of symptoms. The main neuropathological characteristic of HD is the remarkable neurodegeneration of the midline striatal neurons, altering different neurotransmitter systems, such as GABAergic, glutamatergic, dopaminergic, and adenosinergic. Currently, animal models of HD usually use rodents and non-human primates and are classified into genetic and pharmacological models. Among the pharmacological agents, the most commonly tested is the mitochondrial toxin model with the use of 3-nitropropionic acid (3-NPA), that inhibits the mitochondrial complex II-III and is able to reproduce the motor and biochemical alterations occurred in HD. In this context, zebrafish has become an excellent animal model for the study and development of neurodegenerative disease models. In this study, we performed a behavior screening in larval and adult zebrafish to establish the 3-NPA induced HD model. In the larval stage, the treatment consisted of exposure to 3-NPA at concentrations of 0.01, 0.05, 0.1, 0.2 and 0.5 mM for 7 days post-fertilization (dpf). From the 7th dpf to 14th dpf the animals remained only in the water. For the treatment of adult animals, the doses used were 10, 20, and 60 mg/kg and saline for the control group. The treatment consisted of 7 intraperitoneal injections performed every 96 hours.The locomotor and anxiety behavior was assessed 24 hours after each injection and the social interaction, aggression and memory at the end of the 29 days of the treatment. In the larval stage, the exposure to 3-NPA at concentrations of 0.1, 0.2 and 0.5 mM increased the heart rate at 2 and 5 dpf, caused a morphological alteration at the concentration of 0.05 mM and did not alter the locomotor behavior at the ages of 7, 10 and 14 dpf. In the adult stage, the exposure to 3-NPA in the doses at 10, 20, and 60 mg/kg induced a decrease in locomotor activity whereas it had no effect on anxiety and social interaction of the animals. However, the dose of 60 mg/kg caused a decrease in aggressive behavior and a memory impairment in the inhibitory avoidance task. These data suggest that zebrafish in the larval stage is a viable model for studying the characteristics of the pre-manifestation phase of HD and, in the adult stage, we identified through the long-term treatment with 3-NPA a new animal model to study the phenotypic characteristics of the late stage of HD.A Doença de Huntington (DH) é uma condição neurodegenerativa, de herança genética, causada por uma expansão anormal do trinucleotídeo CAG, resultando em uma mutação da proteína huntingtina. É caracterizada por uma tríade de sintomas com alteração progressiva da função motora, cognitiva e psiquiátrica. Os primeiros sintomas normalmente surgem na fase adulta, embora também possam aparecer na idade juvenil, em torno dos 20 anos de idade, sendo assim denominada de DH juvenil. A doença torna-se fatal entre 15 a 20 anos após o aparecimento dos primeiros sintomas. Além disso, a idade do aparecimento e a intensidade dos sintomas estão relacionadas com o número de repetições de CAG, ou seja, quanto mais repetições de CAG, mais cedo a patologia desenvolve-se e maior a intensidade dos sintomas. A principal característica neuropatológica da DH é a notável neurodegeneração dos neurônios médios do estriado, alterando diferentes sistemas de neurotransmissão, tais como GABAérgico, glutamatérgico, dopaminérgico e adenosinérgico. Atualmente, os modelos animais da DH normalmente utilizam roedores e primatas não humanos e são classificados em genéticos e farmacológicos. Dentre os farmacológicos, o mais utilizado é o modelo de toxina mitocondrial com o uso do ácido-3-nitropropiônico (3- NPA), que inibe o complexo II-III mitocondrial e é capaz de reproduzir as alterações motoras e bioquímicas ocorridas na DH. Nesse contexto, o peixe-zebra vem se tornando um excelente modelo animal para o estudo e desenvolvimento de modelos de doenças neurodegenerativas. Neste estudo, realizamos uma triagem comportamental no peixe-zebra em estágio larval e adulto para estabelecer o modelo da DH induzido por 3-NPA. No estágio larval, o tratamento consistiu de exposição ao 3-NPA nas concentrações de 0,01, 0,05, 0,1, 0,2 e 0,5 mM durante 7 dias-pósfertilização (dpf). Do 7º dpf até o 14º dpf, os animais permaneceram somente na água. Para o tratamento dos animais adultos, as doses utilizadas foram 10, 20 e 60 mg/kg e salina para o grupo controle. O tratamento consistiu de 7 injeções via intraperitoneal realizadas a cada 96 horas. O comportamento locomotor e de ansiedade foi avaliado 24 horas após cada injeção e a interação social, agressividade e memória no final do tratamento de 29 dias. Nossos resultados demonstraram que no estágio larval a exposição ao 3-NPA nas concentrações de 0,1, 0,2 e 0,5 mM aumentou a frequência cardíaca analisada aos 2 e 5 dpf, ocasionou alteração morfológica na concentração de 0,05 mM e não alterou o comportamento locomotor avaliado nas idades de 7, 10 e 14 dpf. No estágio adulto, a exposição ao 3-NPA nas doses de 10, 20 e 60 mg/kg induziu a uma diminuição da atividade locomotora, enquanto não houve efeito na ansiedade e interação social dos animais. Entretanto, a dose de 60 mg/kg de 3-NPA causou uma diminuição no comportamento agressivo e um prejuízo de memória na tarefa da esquiva inibitória. Esses dados sugerem que, no estágio larval, o peixe-zebra é um modelo viável para estudar as características da fase de pré-manifestação da DH e, no estágio adulto, identificamos através do tratamento a longo prazo com o 3- NPA um novo modelo animal para estudar as características fenotípicas do estágio tardio da DH.Submitted by PPG Medicina e Ciências da Saúde (medicina-pg@pucrs.br) on 2019-06-04T12:07:34Z No. of bitstreams: 1 Melissa_Talita_Wiprich.pdf: 2197931 bytes, checksum: 3b36343fef3a2a5042ed54f5954eb3cd (MD5)Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2019-06-17T13:32:18Z (GMT) No. of bitstreams: 1 Melissa_Talita_Wiprich.pdf: 2197931 bytes, checksum: 3b36343fef3a2a5042ed54f5954eb3cd (MD5)Made available in DSpace on 2019-06-17T13:37:46Z (GMT). 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dc.title.por.fl_str_mv Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais
title Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais
spellingShingle Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais
Wiprich, Melissa Talita
Locomoção
Ácido-3-nitropropiônico
Doença de Huntington
Memória
Peixe-zebra
Locomotion
3-nitropropionic Acid
Huntington Disease
Memory
Zebrafish
CIENCIAS DA SAUDE::MEDICINA
title_short Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais
title_full Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais
title_fullStr Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais
title_full_unstemmed Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais
title_sort Estabelecimento de um modelo de Doença de Huntington induzido por ácido-3-nitropropiônico em peixe-zebra : avaliação de parâmetros comportamentais
author Wiprich, Melissa Talita
author_facet Wiprich, Melissa Talita
author_role author
dc.contributor.advisor1.fl_str_mv Bonan, Carla Denise
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/8058052532279136
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/3816230343785348
dc.contributor.author.fl_str_mv Wiprich, Melissa Talita
contributor_str_mv Bonan, Carla Denise
dc.subject.por.fl_str_mv Locomoção
Ácido-3-nitropropiônico
Doença de Huntington
Memória
Peixe-zebra
topic Locomoção
Ácido-3-nitropropiônico
Doença de Huntington
Memória
Peixe-zebra
Locomotion
3-nitropropionic Acid
Huntington Disease
Memory
Zebrafish
CIENCIAS DA SAUDE::MEDICINA
dc.subject.eng.fl_str_mv Locomotion
3-nitropropionic Acid
Huntington Disease
Memory
Zebrafish
dc.subject.cnpq.fl_str_mv CIENCIAS DA SAUDE::MEDICINA
description Huntington’s disease (HD) is a neurodegenerative genetic inheritance condition caused by an abnormal expansion of the CAG trinucleotide resulting in a mutation of the huntingtin protein. It is characterized by a triad of symptoms with progressive alterations of motor, cognitive and psychiatric functions. The first symptoms usually appear in the adult phase, but they can also appear in the juvenile age, around the 20 years old, being denominated juvenile HD. The disease becomes fatal 15 to 20 years after the onset of the first symptoms. In addition, the age of onset and intensity of symptoms are related to the number of CAG repeats, i.e. the more CAG repeats, the earlier the pathology develops and the greater the intensity of symptoms. The main neuropathological characteristic of HD is the remarkable neurodegeneration of the midline striatal neurons, altering different neurotransmitter systems, such as GABAergic, glutamatergic, dopaminergic, and adenosinergic. Currently, animal models of HD usually use rodents and non-human primates and are classified into genetic and pharmacological models. Among the pharmacological agents, the most commonly tested is the mitochondrial toxin model with the use of 3-nitropropionic acid (3-NPA), that inhibits the mitochondrial complex II-III and is able to reproduce the motor and biochemical alterations occurred in HD. In this context, zebrafish has become an excellent animal model for the study and development of neurodegenerative disease models. In this study, we performed a behavior screening in larval and adult zebrafish to establish the 3-NPA induced HD model. In the larval stage, the treatment consisted of exposure to 3-NPA at concentrations of 0.01, 0.05, 0.1, 0.2 and 0.5 mM for 7 days post-fertilization (dpf). From the 7th dpf to 14th dpf the animals remained only in the water. For the treatment of adult animals, the doses used were 10, 20, and 60 mg/kg and saline for the control group. The treatment consisted of 7 intraperitoneal injections performed every 96 hours.The locomotor and anxiety behavior was assessed 24 hours after each injection and the social interaction, aggression and memory at the end of the 29 days of the treatment. In the larval stage, the exposure to 3-NPA at concentrations of 0.1, 0.2 and 0.5 mM increased the heart rate at 2 and 5 dpf, caused a morphological alteration at the concentration of 0.05 mM and did not alter the locomotor behavior at the ages of 7, 10 and 14 dpf. In the adult stage, the exposure to 3-NPA in the doses at 10, 20, and 60 mg/kg induced a decrease in locomotor activity whereas it had no effect on anxiety and social interaction of the animals. However, the dose of 60 mg/kg caused a decrease in aggressive behavior and a memory impairment in the inhibitory avoidance task. These data suggest that zebrafish in the larval stage is a viable model for studying the characteristics of the pre-manifestation phase of HD and, in the adult stage, we identified through the long-term treatment with 3-NPA a new animal model to study the phenotypic characteristics of the late stage of HD.
publishDate 2019
dc.date.accessioned.fl_str_mv 2019-06-17T13:37:46Z
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