Efeito da terapia hormonal de longa duração com estrogênio sobre comportamento cognitivo e funcional de ratas Wistar senescentes.
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2023-07-06
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Universidade Estadual Paulista (Unesp)
Resumo
O envelhecimento resulta do declive gradativo funcional celular, programado e pendente de tempo que todos seres vivos propendem passar. Na perimenopausa, uma das fases do envelhecimento reprodutivo, as interações dos neurônios produtores do hormônio liberador de gonadotrofinas (GnRH), gonadotrofinas e esteroides gonadais, e a atividade de neurônios de regiões como o locus coeruleus (LC) e hipocampo (HP) podem comprometer biomarcadores do estado redox, levando a alterações comportamentais e neuroprotetoras. Nossa hipótese é que a terapia hormonal com estrogênio (THE) propicia ação estimuladora e consequente modulação de biomarcadores do estado redox hipocampal, promovendo a manutenção de processos mnemônicos, indução de resposta ansiolítica e melhora da marcha no período do envelhecimento. Para testar esta hipótese, analisamos o perfil ansiolítico, memória de reconhecimento, deambulação, biomarcadores oxidativos, atividade e viabilidade celular do LC e HP de ratas Wistar senescentes. Portanto, nosso objetivo foi análise do comportamento cognitivo e funcional de ratas submetidas ou não a THE na fase da periestropausa. Quarenta ratas participaram do estudo, 20 receberam óleo de milho (grupo 21Me/Ve; óleo de milho/0,2mL/sc; 2x/semana) e 20 foram submetidas a THE (grupo 21Me/E2; 17β-estradiol/15 μg/Kg/sc; 2x/semana) por 120 dias. Testes de campo aberto, labirinto em cruz elevado, reconhecimento de objetos e deambulação foram realizados imediatamente antes e ao final do período de tratamento. Dos encéfalos decapitados os hipocampos isolados foram destinados a análises bioquímicas, por sua vez, encéfalos perfundidos foram destinados para análises histológicas das regiões CA1, CA3 e GD hipocampais e LC. Animais do Grupo 21Me/E2 apresentaram tempo total, frequência de entradas significantemente maior nos braços abertos e região central do campo aberto, além de maior locomoção do mesmo em relação ao grupo 21Me/Ve, exibindo perfil ansiolítico em geral. No teste de reconhecimento de objetos, o grupo 21Me/Ve apresentou diminuição na memória de longo prazo e as ratas do grupo 21Me/E2 mantiveram-se com mesmo índice como aos 17 meses de idade além de melhor equilíbrio do estado redox hipocampal. Nossos resultados mostraram diminuição no comprimento e maior largura da passada dos animais aos 21 meses de idade, que foi revertido para aqueles que receberam T HE, bem como, atuando sobre prevenção à perda celular neuronal. Este estudo fornece evidências da eficácia do THE, mostrando que mudanças significativas ocorrem na etologia, biomecânica e bioquímica cerebral de ratas naturalmente envelhecidas durante a senescência ovariana. Portanto, nossos resultados sugerem que a administração de E2 exógeno é necessária, especialmente no período de intensa irregularidade do ciclo, para restabelecer as funções realizadas, bem como possibilitar a exploração progressiva da terapia como recurso preventivo para distúrbios neuropsicológicos e distúrbios neurodegenerativos.
Aging results from the gradual functional cellular decline, programmed and dependent on time that all living beings tend to go through. In perimenopause, one of the stages of reproductive aging, the interactions of neurons producing gonadotropin-releasing hormone (GnRH), gonadotropins and gonadal steroids, and the activity of neurons in regions such as the locus coeruleus (LC) and hippocampus (HP) can compromise biomarkers of the redox state, leading to behavioral and neuroprotective changes. Our hypothesis is that hormone therapy with estrogen (EHT) provides a stimulating action and consequent modulation of biomarkers of the hippocampal redox state, promoting the maintenance of mnemonic processes, inducing anxiolytic response and improving gait in the aging period. To test this hypothesis, we analyzed the anxiolytic profile, recognition memory, ambulation, oxidative biomarkers, activity and cell viability of LC and HP of senescent Wistar rats. Therefore, we aimed to analyze the cognitive and functional behavior of rats submitted or not to EHT in the periestropause phase. Forty female rats participated in the study, 20 were treated with corn oil (group 21Mo/Veh; corn oil/0.2mL/sc; 2x/week) and 20 were submitted to EHT (group 21Mo/E2; 17β-estradiol/15 μg/Kg/sc; 2x/week) for 120 days. Open field, elevated plus maze, object recognition, and ambulation tests were performed immediately before and at the end of the treatment period. The hippocampus was isolated from decapitated brains and destined for biochemical analysis, in turn, perfused brains were destined for histological analysis of the hippocampus CA1, CA3 and GD regions and LC. Animals from the 21Mo/E2 group showed a significantly higher total time, frequency of entries into the open arms and central region of the open field, in addition to greater locomotion in relation to the 21Me/Ve group, showing an anxiolytic profile in general. In the object recognition test, the 21Mo/Veh group showed a decrease in long-term memory and the rats in the 21Mo/E2 group maintained the same index as at 17 months of age, in addition to a better balance of the hippocampal redox state. Our results showed a decrease in the length and greater width of the animals' stride at 21 months of age, which was reversed for those who received EHT, as well as acting on the prevention of neuronal cell loss. This study provides evidence of the efficacy of EHT, showing that significant changes occur in the ethology, biomechanics and brain biochemistry of naturally aged female rats during ovarian senescence. Therefore, our results suggest that the administration of exogenous E2 is necessary, especially in the cycle's period of intense irregularity, to reestablish the normal functions, as well as to allow the progressive exploration of the therapy as a preventive resource for neuropsychological disorders and neurodegenerative disorders.
Aging results from the gradual functional cellular decline, programmed and dependent on time that all living beings tend to go through. In perimenopause, one of the stages of reproductive aging, the interactions of neurons producing gonadotropin-releasing hormone (GnRH), gonadotropins and gonadal steroids, and the activity of neurons in regions such as the locus coeruleus (LC) and hippocampus (HP) can compromise biomarkers of the redox state, leading to behavioral and neuroprotective changes. Our hypothesis is that hormone therapy with estrogen (EHT) provides a stimulating action and consequent modulation of biomarkers of the hippocampal redox state, promoting the maintenance of mnemonic processes, inducing anxiolytic response and improving gait in the aging period. To test this hypothesis, we analyzed the anxiolytic profile, recognition memory, ambulation, oxidative biomarkers, activity and cell viability of LC and HP of senescent Wistar rats. Therefore, we aimed to analyze the cognitive and functional behavior of rats submitted or not to EHT in the periestropause phase. Forty female rats participated in the study, 20 were treated with corn oil (group 21Mo/Veh; corn oil/0.2mL/sc; 2x/week) and 20 were submitted to EHT (group 21Mo/E2; 17β-estradiol/15 μg/Kg/sc; 2x/week) for 120 days. Open field, elevated plus maze, object recognition, and ambulation tests were performed immediately before and at the end of the treatment period. The hippocampus was isolated from decapitated brains and destined for biochemical analysis, in turn, perfused brains were destined for histological analysis of the hippocampus CA1, CA3 and GD regions and LC. Animals from the 21Mo/E2 group showed a significantly higher total time, frequency of entries into the open arms and central region of the open field, in addition to greater locomotion in relation to the 21Me/Ve group, showing an anxiolytic profile in general. In the object recognition test, the 21Mo/Veh group showed a decrease in long-term memory and the rats in the 21Mo/E2 group maintained the same index as at 17 months of age, in addition to a better balance of the hippocampal redox state. Our results showed a decrease in the length and greater width of the animals' stride at 21 months of age, which was reversed for those who received EHT, as well as acting on the prevention of neuronal cell loss. This study provides evidence of the efficacy of EHT, showing that significant changes occur in the ethology, biomechanics and brain biochemistry of naturally aged female rats during ovarian senescence. Therefore, our results suggest that the administration of exogenous E2 is necessary, especially in the cycle's period of intense irregularity, to reestablish the normal functions, as well as to allow the progressive exploration of the therapy as a preventive resource for neuropsychological disorders and neurodegenerative disorders.
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Palavras-chave
Envelhecimento, Estrogênios, Hipocampo (Cerebro), Locus coeruleus, Estrogens