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Previous issue date: 2014-02-27 / Introduction: Psychiatric disorders are among the most common diseases and represent an important public health problem. The neurobiological processes implicated in the pathophysiology of neuropsychiatric disorders are not fully known. Exposure to adverse events in early life increases the risk of developing neuropsychiatric conditions in adulthood, including affective disorders and psychosis. In rodents, maternal separation (MS) is commonly used as a model of exposure to stress in early life. MS may cause long-term effects on brain function, including cellular, neurochemical and behavioral changes. The involvement of pro -inflammatory cytokines in neuropsychiatric disorders has attracted increasing interest from researchers. Topiramate is an antiepileptic drug that has proven to exhibit neuroprotective properties in animal models of brain injury, reducing neuronal damage in animal models of neonatal hypoxic ischemia and attenuating memory deficits. Objectives: To investigate the effect of Topiramate (Top) in reversing cognitive impairment in rats submitted to neonatal stress induced by MS and compare with Valproic Acid (Val), which was previously studied by our research group. Furthermore, to investigate the effects of neonatal stress with and without treatment with Val and Top on BDNF, TNF- α, and Interleukin 10 (IL-10) levels. Methodology: Study on animal model of stress exposure in neonatal period (method of MS), in male rats. Treatment with Top and Val in adulthood: one group received 10mg/kg of Top orally once a day for 14 days, the other group received 100mg/kg of Top in the same period, another group received Val 200mg/kg orally in the same period, and the other group received the same corresponding amount in milliliters also orally of saline solution (control group). Behavioral tests (motor/exploratory activity, recognition memory), and analyzes of BDNF, TNF- α , and IL-10 levels were performed in adulthood. Results: The MS during the neonatal period causes memory impairment in adult rats. The treatment in adults with Top caused injury to memory when used, independently of maternal separation. Likewise, it also failed to reverse the damage caused by MS. Pharmacological treatment with Val in adulthood reversed long-term (LTM) memory deficits induced by MS and caused an improvement in short-term memory (STM) in rats separated from the mother. The MS induced a significant increase in IL -10 when the separated-saline (MS - Sal) was compared with the control group (non-separated-saline, NS-Sal). Statistical comparisons of TNF-α levels, indicated that the group subjected to MS which received saline (MS - Sal) showed a significant increase in the levels of TNF-α in the hippocampus when compared with the control group. Similarly, the levels of TNF-α in the group MS-Sal were also increased in cortex, compared to NS-Sal group. The MS induced a significant decrease in BDNF levels in the hippocampus, when the group MS-Sal was compared with the control group. No statistically significant difference was observed in the comparison of BDNF in prefrontal cortex. Conclusions: MS leads to persistent memory deficits and increases levels of the anti-inflammatory cytokine, IL-10, and of the pro-inflammatory cytokine, TNF-α, and decreases levels of BDNF in adulthood. Val partially alleviated these memory deficits, while Top was ineffective. Surprisingly, the two drugs were able to recover levels of cytokines in brain regions studied. / Introdu??o: Os transtornos psiqui?tricos est?o entre as doen?as mais comuns e representam um importante problema de sa?de p?blica. Os processos neurobiol?gicos implicados na fisiopatologia dos transtornos neuropsiqui?tricos ainda n?o s?o totalmente conhecidos. A exposi??o a eventos adversos no in?cio da vida aumenta o risco de desenvolvimento de condi??es neuropsiqui?tricas na idade adulta, incluindo transtornos afetivos e psicose. Em roedores, a separa??o materna (SM) tem sido correntemente utilizada como um modelo de exposi??o ao estresse no in?cio da vida. A SM poder causar efeitos ? longo prazo na fun??o cerebral, incluindo altera??es celulares, neuroqu?micas e comportamentais. O envolvimento das citocinas pr? e antiinflamat?rias nas doen?as psiqui?tricas tem despertado cada vez mais o interesse dos pesquisadores. O topiramato ? um medicamento anti-epil?ptico que provou apresentar propriedades neuroprotetoras em modelos animais de les?o cerebral, reduzindo o dano neuronal em modelos animais de isquemia hip?xica neonatal e atenuando os d?ficits da mem?ria. Objetivos: Investigar o efeito do Topiramato (Top) na preven??o do preju?zo cognitivo em ratos Wistar submetidos a estresse neonatal, induzido pela SM e comparar com o ?cido Valpr?ico (Val). Investigar o efeito do estresse neonatal com e sem o tratamento com Top e Val sobre os n?veis de BDNF, TNF- α e Interleucina 10 (IL-10). Metodologia: Estudo com modelo animal de exposi??o a estresse no per?odo neonatal (m?todo SM), em ratos machos. Tratamento com Top e Val na idade adulta: um grupo recebeu 10mg/Kg via oral de Top uma vez ao dia por 14 dias, o outro grupo recebeu 100mg/kg de Top no mesmo per?odo, outro grupo recebeu 200mg/kg via oral de Val no mesmo per?odo, e o outro grupo recebeu a mesma quantidade correspondente em mililitros tamb?m por via oral de solu??o salina (grupo controle). Testes comportamentais (atividade motora/explorat?ria, mem?ria), an?lises de BDNF, TNF α, IL10 foram realizados na idade adulta. Resultados: A SM durante o per?odo neonatal causa preju?zo de mem?ria em ratos adultos. O tratamento na idade adulta com Top ocasionou preju?zo ? mem?ria quando utilizado independente da SM. Assim como, tamb?m n?o conseguiu reverter os danos ocasionados pela SM. O tratamento farmacol?gico com Valproato (Val) na vida adulta reverteu os d?ficits de mem?ria de longa- dura??o (LTM) induzidos pela priva??o materna e provocou uma melhora na mem?ria de curta-dura??o (STM) nos ratos separados da m?e. A SM induziu um aumento significativo nos n?veis de IL-10 quando o grupo separado-salina (S Sal) foi comparado com o grupo controle n?o separado-salina (NS-Sal). As compara??es estat?sticas dos n?veis de TNF-α, indicaram que o grupo submetido ? SM que recebeu solu??o salina (S-Sal) apresentou um aumento significativo nos n?veis de TNF-α no hipocampo quando comparado com o grupo de controle. Do mesmo modo, os n?veis de TNF-α de animais do grupo S -Sal foram tamb?m aumentados no c?rtex, quando comparado com o grupo de NS Sal. A SM induziu um decr?scimo significativo nos n?veis de BDNF no hipocampo, quando o grupo S-Sal foi comparado com o grupo controle. Nenhuma diferen?a estatisticamente significativa foi observada na compara??o do BDNF no c?rtex pr?-frontal. Conclus?es: A SM induz a d?ficits de mem?ria persistentes e aumenta os n?veis da citocina anti-inflamat?ria, a IL-10, e da citocina pr? - inflamat?ria, o TNF-α, e diminui os n?veis de BDNF na idade adulta. O Val parcialmente amenizou esses d?ficits de mem?ria, enquanto que o Top foi ineficaz. Surpreendentemente, as duas drogas foram capazes de recuperar os n?veis das citocinas nas regi?es cerebrais estudadas.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/1770 |
| Date | 27 February 2014 |
| Creators | Pinheiro, Rose Mary Carvalho |
| Contributors | Schr?der, Nadja |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Medicina e Ci?ncias da Sa?de, PUCRS, BR, Faculdade de Medicina |
| 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 | 7620745074616285884, 500, 600, -8624664729441623247 |
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