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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2021.tde-27092021-115850
Document
Author
Full name
Lilian do Amaral
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2021
Supervisor
Committee
Santos, Antonio Cardozo dos (President)
Marques, Vanessa Bergamin Boralli
Padovan Neto, Fernando Eduardo
Tirapelli, Carlos Renato
Title in Portuguese
Neuritogênese induzida pela doxiciclina: estudo das vias de sinalização e do efeito protetor em modelo in vitro associado à doença de Parkinson
Keywords in Portuguese
Células PC12
Doença de Parkinson
Doxiciclina
Neuritogênese
Neuroplasticidade axonal
Abstract in Portuguese
As tetraciclinas de segunda geração, como a doxiciclina, foram introduzidas nos anos 60, sendo amplamente usadas como antibióticos até hoje. A doxiciclina é capaz de atravessar a barreira hematoencefálica e induzir efeitos distintos da sua atividade antibiótica. Estudos anteriores sugerem o potencial neuroprotetor da doxiciclina, porém o envolvimento da atividade neurotrófica nesse efeito não foi ainda avaliado. O efeito neurotrófico é uma ferramenta importante na neuroproteção, considerando-se o papel da degeneração axonal nos estágios iniciais das doenças neurodegenerativas, incluindo a doença de Parkinson. Assim, este estudo visou investigar a ação da doxiciclina nas vias de sinalização da neuritogênese, bem como seu possível efeito neuroprotetor em modelo in vitro de neurotoxicidade induzida pela neurotoxina dopaminérgica MPP+ em células PC12. Essas células constituem um modelo apropriado para a avaliação da diferenciação neuronal, pois respondem ao NGF (fator de crescimento neuronal) emitindo neuritos (precursores de axônios e dendritos) e adquirindo características de neurônios simpáticos. Os resultados indicam que a doxiciclina induz a neuritogênese através da ativação do receptor trkA e das vias de sinalização neurotrófica PI3K/Akt e MAPK/ERK, promovendo o aumento da expressão de proteínas associadas à plasticidade axonal e sináptica (sinapsina I, GAP-43 e NF-200). Ainda, a doxiciclina protege as células PC12 contra a regulação negativa induzida pelo MPP+ em proteínas axonais (GAP-43, NF-200) e do citoesqueleto (βIII-tubulina). Sinaptofisina, F-actina e moduladores da bioenergética não são alvos moleculares da doxiciclina. Em conjunto, os resultados indicam o potencial neurotrófico da doxiciclina, bem como a participação desse mecanismo de ação na sua atividade neuroprotetora. Esses achados são promissores e sugerem que a doxiciclina pode promover regeneração axonal nos processos neurodegenerativos. Estudos adicionais são necessários para comprovar esse efeito.
Title in English
Neuritogenesis induced by doxycycline: study of signaling pathways and the protective effect in an in vitro model associated with Parkinson's disease
Keywords in English
Axonal neuroplasticity
Doxycycline
Neuritogenesis
Parkinson's disease
PC12 cells
Abstract in English
Second-generation tetracyclines, such as doxycycline, were introduced in the 1960s and are widely used as antibiotics until today. Doxycycline is able to cross the blood-brain barrier and induce distinct effects from its antibiotic activity. Previous studies suggest the neuroprotective potential of doxycycline, but the involvement of neurotrophic action in this effect has not yet been evaluated. The neurotrophic effect is an important tool for neuroprotection, considering the role of axonal degeneration in the early stages of neurodegenerative diseases, including Parkinson's disease. Thus, this study aimed to investigate the action of doxycycline on neurotrophic signaling pathways, as well as its possible neuroprotective effect in an in vitro model of neurotoxicity induced by the dopaminergic neurotoxin MPP+ in PC12 cells. These cells constitute an appropriate model for the assessment of neuronal differentiation, as they respond to NGF (Nerve Growth Factor) by emitting neurites (precursors of axons and dendrites) and acquiring characteristics of sympathetic neurons. The results indicate that doxycycline induces neuritogenesis through activation of the trkA receptor and neurotrophic signaling pathways PI3K/Akt and MAPK/ERK, promoting increased expression of proteins associated with axonal and synaptic plasticity (synapsin I, GAP-43 and NF-200). In addition, doxycycline protects PC12 cells against negative regulation induced by MPP+ in axonal (GAP-43, NF-200) and cytoskeletal (βIII-tubulin) proteins. Synaptophysin, F-actin and bioenergetic modulators are not molecular targets of doxycycline. Altogether the results indicate the neurotrophic potential of doxycycline, as well as the participation of this action mechanism in its neuroprotective activity. These findings are promising and suggest that doxycycline might induce axonal regeneration in neurodegenerative processes. Further studies are needed to confirm this effect.
 
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Release Date
2023-05-07
Publishing Date
2021-09-28
 
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