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Previous issue date: 2013-08-23 / Modafinil is a drug that promotes increased alertness. It was approved for the treatment of excessive daytime sleepness in narcolepsy and obstructive sleep apnea. Some studies indicate that Modafinil can improve learning, memory and reverse cognitive loss induced by sleep deprivation and stress. This study was aimed to characterize the effects of modafinil on control adult rat s memory. Further, its effects were also studied using three models of cognitive decline to assess modafinil effects on memory. The iron overload model on neonatal period related to the degenerative diseases, maternal deprivation on neonatal period that generates emotional and cognitive impairment on adulthood, and, paradoxal sleep deprivation, which is known to interfere with on memory consolidation. The first experiment investigated the effects of the drug on memory consolidation and retrieval using distinct paradigms of learning; object recognition and inhibitory avoidance (aversive memory task) in healthy adult rats. Male Wistar rats received a single injection of acute modafinil (0.0; 0.75; 7.5 or 75 mg/kg) immediately after training or one hour before object recognition or inhibitory avoidance retention tests. Acute administration of modafinil to healthy rats did not affect memory consolidation or retrieval. The second experiment examined the acute or chronic administration of modafinil on the reversal of memory deficits induced by iron overload in the neonatal period, a model of cognitive decline related to neurodegenerative disorders. Rats treated with iron between 12 and 14 postnatal days received in adulthood, acute intraperitoneal injection of modafinil (0.0; 0.75; 7.5 and 75 mg/kg) immediately after training in the recognition task object. A single injection of modafinil at the highest dose was able to recover recognition memory in rats treated with iron. In order to investigate the effects of chronic treatment with modafinil, irontreated rats received intraperitoneal injections of modafinil at the same doses for seventeen days. Twenty-four hours after the last injection, the animals were submitted to object recognition or inhibitory avoidance training. Memory retention tests were performed twenty four hours after training. Chronic administration of modafinil fully recovered memory deficits induced by iron both in recognition memory and emotional memory. Experiment III evaluated the effects of maternal deprivation combined with paradoxical sleep deprivation (PSP) on recognition memory. Wistar rats separated from their mothers for fourteen days, three hours per day, underwent PSP for twenty four hours in adulthood. The model allowed to investigate the ability to reverse such deficits with administration of modafinil that was effective in restoring cognitive decline caused by maternal deprivation and PSP. The use and commercialization of modafinil as a stimulant is widely proved. To support its application in the memory loss associated with neurodegenerative disorders, stress in early life and PSP, additional preclinical and clinical research are needed. This study shows, however, through the proposed models of cognitive decline, the drug effectiveness in reversing such memory deficits. / O Modafinil ? um f?rmaco que promove o aumento do estado de alerta, e foi aprovado para o tratamento da sonol?ncia diurna excessiva na narcolepsia e apn?ia obstrutiva do sono. Alguns estudos indicam que o modafinil pode melhorar a aprendizagem, a mem?ria e reverter d?ficits cognitivos induzidos pela priva??o de sono e estresse. No presente trabalho tivemos como objetivo caracterizar os efeitos do modafinil sobre a mem?ria em ratos adultos saud?veis. Al?m disso, seus efeitos tamb?m foram estudados utilzando-se tr?s modelos de decl?nio cognitivo para avaliar os efeitos do modafinil sobre a mem?ria: o modelo da sobrecarga de ferro no per?odo neonatal relacionado com as doen?as neurodegenerativas, a separa??o materna no per?odo neonatal que gera um preju?zo emocional e cognitivo na idade adulta e, por fim, a priva??o de sono paradoxal que interfere na consolida??o da mem?ria. No experimento I foram investigados os efeitos do f?rmaco sobre a consolida??o e a evoca??o da mem?ria utilizando-se distintos paradigmas de aprendizagem: reconhecimento de objetos e esquiva inibit?ria (tarefa de mem?ria aversiva) em ratos adultos saud?veis. Ratos Wistar adultos receberam uma inje??o aguda de modafinil (0,75; 7,5 ou 75 mg/kg) ou ve?culo imediatamente ap?s o treino ou 1 hora antes do teste nas tarefas de reconhecimento de objetos ou de esquiva inibit?ria. A administra??o aguda de modafinil em ratos saud?veis n?o afetou a consolida??o e nem a evoca??o da mem?ria. O experimento II analisou os efeitos da administra??o aguda ou cr?nica de modafinil sobre os d?ficits de mem?ria induzidos pela sobrecarga de ferro no per?odo neonatal, um modelo de decl?nio cognitivo relacionado a dist?rbios neurodegenerativos. Ratos tratados com ferro entre o 12? e 14? dia p?s natal receberam, na idade adulta, uma inje??o intraperitoneal aguda de modafinil (0,75; 7,5 e 75 mg/kg) ou ve?culo imediatamente ap?s o treino da tarefa de reconhecimento de objeto. Uma inje??o aguda de modafinil na dose mais elevada foi capaz de recuperar a mem?ria de reconhecimento em ratos tratados com ferro. A fim de investigar os efeitos do tratamento cr?nico com modafinil, os ratos tratados com ferro receberam inje??es di?rias de modafinil nas mesmas doses por 17 dias. Vinte e quatro horas ap?s a ?ltima inje??o, os animais foram submetidos ?s tarefas de reconhecimento de objetos e esquiva inibit?ria. Os testes de reten??o de mem?ria foram realizados 24 horas ap?s o treino. A administra??o cr?nica de modafinil recuperou completamente os d?ficits de mem?ria induzidos pelo ferro, tanto na mem?ria de reconhecimento quanto na mem?ria emocional. O experimento III avaliou os efeitos da separa??o materna combinada com a priva??o de sono paradoxal (PSP) sobre a mem?ria de reconhecimento. Ratos Wistar separados da m?e durante 14 dias, tr?s horas por dia, foram submetidos a PSP por vinte e quatro horas na idade adulta. O modelo permitiu investigar a capacidade de revers?o de tais d?ficits com a administra??o de modafinil que foi efetivo em recuperar o decl?nio cognitivo causado pela separa??o materna e pela PSP. A utiliza??o e a comercializa??o do modafinil como estimulante s?o amplamente fundamentadas. Para dar suporte ? sua aplica??o na perda de mem?ria associada ?s perturba??es neurodegenerativas; ao estresse no in?cio da vida e ? PSP, pesquisas pr? cl?nicas e cl?nicas adicionais s?o necess?rias. Este estudo comprova por meio dos modelos de decl?nio cognitivo propostos, a efetividade do f?rmaco em reverter tais d?ficits de mem?ria.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/5481 |
| Date | 23 August 2013 |
| Creators | Garcia, Vanessa Atha?de |
| Contributors | Schr?der, Nadja |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, BR, Faculdade de Bioci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8198246930096637360, 600, 600, 36528317262667714 |
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