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Master's Dissertation
DOI
https://doi.org/10.11606/D.17.2020.tde-25082020-093918
Document
Author
Full name
Davi Silveira Scomparin
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2020
Supervisor
Committee
Campos, Alline Cristina de (President)
Oliveira, Antônio Carlos Pinheiro de
Sebollela, Adriano Silva
Title in Portuguese
Envolvimento da PI3Kγ no efeito amnésico induzido pela escopolamina em camundongos
Keywords in Portuguese
Escopolamina
Hipocampo
Memória
PI3K
Abstract in Portuguese
Estudos mostram que diferentes doses do fármaco escopolamina (ESC) são capazes de gerar amnésia anterógrada em modelos animais, porém ainda não se sabe muito acerca do mecanismo exato pelo qual essa atividade é exercida. A proteína PI3K participa na regulação de uma série de processos intracelulares e é dividida em várias classes e tipos. Sua representante da classe Ib, denominada PI3Kγ, demonstra estar envolvida em processos relacionados ao sistema nervoso central. Dessa forma, a hipótese de trabalho do presente estudo é que a proteína PI3Kγ e as vias por ela reguladas possam estar envolvidas no efeito amnésico anterógrado gerado pela ESC. Para testar tal hipótese, foram utilizados camundongos machos e fêmeas (idade entre 10-12 semanas) knock-out (KO) para a proteína PI3Kγ e camundongos wild-type (WT). O teste de reconhecimento de objetos (TRO) foi utilizado para avaliar as respostas mnemônicas dos animais e a ESC (1 e 2 mg/kg) foi administrada antes da etapa de aquisição do teste. Em um grupo separado, o antagonista seletivo para PI3Kγ denominado AS605240 (Veículo, 3 nM, 10 nM e 30 nM) foi injetado de maneira intrahipocampal apenas em animais WT canulados, sendo também injetado pareado a ESC. ESC, na dose de 1 mg/kg, gerou uma significativa redução do índice de discriminação entre os objetos no TRO em animais WT, mas esse efeito não foi observado em animais KO para PI3Kγ, tanto machos quanto fêmeas. Não houve diferença comportamental correspondente a nenhuma concentração usada para a injeção central apenas de AS605240 no TRO. Quando injetado previamente à ESC, AS605240 na dose de 30 nM não foi efetivo em prevenir o efeito amnésico no TRO. Na região hipocampal, a expressão de proteínas vinculadas a vias associadas a PI3Kγ (mTOR, Akt e associadas a via das MAP Kinases, tais como a Erk) foi analisada. Nesse panorama, foi verificado que animais PI3Kγ KO apresentavam níveis de expressão alterados da proteína Erk e Akt, mas não da proteína mTOR. Juntos, estes dados demonstram que a PI3Kγ está envolvida no mecanismo de ação da amnésia anterógrada induzida por ESC.
Title in English
PI3Kγ participates in the amnesic effect induced by scopolamine in mice
Keywords in English
Hippocampus
Memory
PI3K
Scopolamine
Abstract in English
Scopolamine (SCO), an antagonist of muscarinic receptors, induces anterograde amnesia in animal models, but the exact mechanism associated with this action remains unclear. The PI3K is a family of kinase proteins that play a role in regulating several intracellular processes and classified in 3 different classes. The PI3Kγ is the member of class Ib and can control immune responses and central nervous system functions. Therefore, this study hypothesizes that the PI3Kγ protein and its downstream signaling pathways are involved in the anterograde amnesia induced by SCO. Male and female mice (10-12 weeks old) knock-out (KO) for the PI3Kγ protein and their wild-type (WT) littermates were used. The mnemonic function of the animals was addressed with the novel object recognition test (NOR). SCO (1 and 2 mg/kg) was administered before the acquisition step of the NOR protocol. A separate group of WT mice received an intra-hippocampal treatment with the selective PI3Kγ antagonist AS605240 (Vehicle, 3 nM, 10 nM, and 30 nM) in the acquisition phase of the NOR protocol and this pharmacological intrahippocampal inhibition of PI3Kγ (at the highest concentration tested) was paired with SCO treatment as well. Both in male and female mice, the treatment with SCO (1 mg/kg) induced a significant decrease in the discrimination index between the novel and familiar objects in the NOR test in WT mice, but this effect was absent in PI3Kγ KO mice. None of the concentrations of AS605240 injected into the hippocampus altered the behavioral response of mice in the NOR test. The highest ineffective concentration tested (30nM), therefore, was administered before SCO treatment, however, AS605240 was not able to prevent the anterograde amnesia induced by SCO. The expression of proteins associated with the PI3Kγ pathway (mTOR, Akt, and the MAP kinase-associated protein Erk) in the hippocampal formation was analyzed. Compared to their WT littermates, the PI3K KO mice presented altered hippocampal levels of Erk and Akt, but not mTOR. Our results support that the PI3Kγ protein and its signaling pathways are involved in the anterograde amnesia induced by SCO in mice.
 
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Publishing Date
2020-10-26
 
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