Papel evolutivo da disfunção mitocondrial farmacologicamente induzida pela rotenona em alterações oxiinflamatórias e comportamentais de Eisenia fetida

• Ano de defesa: 2022
• Autor(a) principal: Mastella, Moisés Henrique
• Orientador(a): Cruz, Ivana Beatrice Mânica da
• Banca de defesa: Bochi, Guilherme Vargas, Prigol, Marina, Brucker, Natália, Azzolin, Verônica Farina
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Santa Maria; Centro de Ciências da Saúde
• Programa de Pós-Graduação: Programa de Pós-Graduação em Farmacologia
• Departamento: Farmacologia
• País: Brasil
• Palavras-chave em Português: Sistema nervoso central; Mitocôndria; Minhoca; Carbonato de lítio
• Palavras-chave em Inglês: Central nervous system; Mitochondria; Earthworm; Lithium carbonate
• Área do conhecimento CNPq: CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: http://repositorio.ufsm.br/handle/1/27577

The pathogenesis of neurological diseases such as major depression and Parkinson's disease remains incompletely understood. These diseases are chronic and non-communicable (NCDs), resulting from exposure to one or more stressors and related to mitochondrial dysfunction (MitD), an event that causes the production of reactive oxygen species, resulting in oxy-inflammatory, physiological and behavioral changes. Aiming to understand whether the development and progression of MitD events are evolutionarily conserved and whether they could be pharmacologically attenuated, the earthworm Eisenia fetida was used, inducing MitD events via exposure to rotenone and verifying the potential of lithium carbonate (LC) in the modulation of the resulting changes. Two complementary studies were generated from this proposition, where: (1) it was verified whether MitD, caused by chronic exposure of 14 days to rotenone, is evolutionarily conserved in E. fetida, and (2) whether the LC is capable of modulating the changes resulting from this exposure. In the first study, chronic exposure of 14 days in artificial soil was used. Flow cytometry indicated modulation of populations and cell cycle of coelomic cells when exposed to rotenone (30 nM), while histology indicated anatomical alterations in the ventral nervous ganglion. Brown pigment deposits were observed in the circular muscles, as well as upregulation of the EaTLR gene and downregulation of the ND1 gene. The data suggest that the chronic exposure process reaches its peak on the seventh day and that, after that, the animals initiate organic restoration events. However, the behavioral boric acid avoidance test confirmed the inefficiency in decision-making due to neurodegenerative events and sensory deficits resulting from MitD. The second study involved, in addition to the protocols presented in the first, new methodologies developed. The analyzes were divided into three stages: (1) the safety indicators indicated the dose of choice for the LC in a concentration-effect curve based on the drug's package insert. Next, (2) efficacy indicators were evaluated against individual and concomitant exposure to LC (12.85 mg/mL) and rotenone (30 nM) using ex vivo and in vivo methods. Finally, prostomium culture was the methodology used to evaluate the (3) causal mechanism through molecular analysis. Although some anatomical changes have been reported, the LC was able to positively modulate the damage caused by exposure to rotenone. In behavior, despite the protective effect, there was no acceleration of the organic restoration process. Molecular data are heterogeneous and mostly corroborate with the scientific literature, showing anti-inflammatory patterns when in the presence of LC, and damage when in rotenone. Thus, the general panorama evaluated in this thesis confirms the evolutionary character of MitD, since the alterations presented in a pioneering organism, both ex vivo and in vivo, are also visualized in derived groups. Rotenone continues to be an excellent model for inducing MitD, emphasizing its role in studies of the central nervous system (CNS), and which, when associated with the use of annelids, may represent an alternative and complementary line for research involving NCDs related to the CNS.