Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in cognitive function. Intracerebroventricular injection of streptozotocin (icv-STZ) has been used as an experimental model of Sporadic AD (SAD) in rodents and represents a promising tool for etiopathogenic analysis and evaluation of new therapeutic proposals for AD. The icv-STZ model shows many aspects of SAD abnormalities, resulting in decreased brain glucose and energy metabolism, cognitive impairment, oxidative stress, neuronal loss, and amyloid angiopathy. Royal jelly (RJ), a substance produced by worker honeybees of the Apis mellifera species, has been popularly used for more than 30 years in areas related to health eating and natural medicine. Researches indicate that RJ has a several pharmacological activities, including neuroprotective and improvement of cognitive function. The objective of this study was to investigate the effects of oral treatment with royal jelly during 2 weeks in Wistar rats submitted to icv-STZ on a working memory and neuroprotection, as evaluated by neurogenesis, neurodegeneration and oxidative stress. In this study, icv-STZ injection induced deleterious effects in the hippocampus, associated with cognitive impairments, and developed marked neurodegeneration, besides the reduction of neurogenesis and increased oxidative stress. On the other hand, RJ long-term oral administration induced beneficial effects in animals injured by icv-STZ injection, increasing retention time for working spatial memory, reducing neurodegeneration and oxidative stress level and increasing the proliferation of new neurons in the hippocampus. Thus, RJ promotes beneficial effects on cognitive functions and exhibits a neuroprotective action in the STZ experimental model of SAD.

Agradeço à Deus Pai Mãe Vida Consciência pela existência e oportunidade de desfrutar a Vida. À minha esposa Karen Roedel por todo amor, companheirismo, amizade e alegria que vivenciamos diariamente. Agora somos uma Happy Family! Seu apoio, compreensão e incentivo oferecidos em tantas e tantas horas foram essenciais para que eu conseguisse chegar até aqui. Como é bom ter você ao meu lado na estrada da vida!!! Aos meus pais José Evanildo da Silva e Maria Teresa Guardia de Souza e seus respectivos companheiros Wilma Conceição e Marco Roma por todo amor, amizade, exemplos, apoio e incentivo dados ao longo da vida. À minha orientadora prof a. Dra. Maria Regina Lopes Sandoval pela confiança e oportunidade de realização deste projeto de pesquisa. Agradeço por todos os ensinamentos e orientações ao longo deste percurso. Desejo que este nosso projeto de pesquisa possa gerar bons frutos. Além de todos os aprendizados obtidos, me sinto feliz pela amizade construída. Ao prof. Dr. Luiz Roberto Giorgetti de Britto (ICB-USP) por toda colaboração, conselhos e disponibilidade do laboratório para realização das análises histológicas. Ao prof. Dr. Gilberto Fernando Xavier (IB-USP) por toda colaboração e orientação no delineamento experimental dos testes comportamentais. Ao prof a. Dra. Solange Castro Afeche (Lab. Farmacologia-Instituto Butantan) pela colaboração com as sugestões dadas ao longo do desenvolvimento deste trabalho. Aos professores Dr. André Frazão Helene (IB-USP) e Dr. José Cipolla Neto (ICB-USP) por todas contribuições realizadas durante o exame de qualificação e esclarecimentos durante o processo de elaboração da dissertação. À toda equipe de funcionários e pesquisadores do Laboratório de Farmacologia do Instituto Butantan. Em especial, agradeço à Elisa por me acompanhar de perto nas atividades do diaa-dia, me auxiliando nos experimentos, ensinando coisas e cultivando a amizade com conversas descontraídas. À Andrea por todo auxílio e explicações que me guiaram quando cheguei no laboratório, e também pelo apoio sempre oferecidos. À Renata, Otacília, seu Antônio e a todos que também me auxiliaram em momentos significativos. À todos os alunos do Laboratório de Farmacologia do Instituto Butantan. Aprendi um pouco com cada um, e também me diverti bastante.

Here, we investigate the effects of obesity induced by monosodium glutamate (MSG) on cognitive impairment and whether this model induces any alteration in the affinity, density, and subtypes of muscarinic acetylcholine receptors (mAChRs) in rat hippocampus. Healthy rats were used as controls, and MSG-obese rats were selected via the Lee index > 0.300. The effects of MSG-induced obesity on hippocampal spatial learning and memory processes were evaluated by using the working memory versions of the Morris’ water maze task and the evaluation of mAChRs by binding assay and their subtypes by immunoprecipitation assays. [3H]Quinuclidinyl benzilate specific binding analysis showed that the equilibrium dissociation constant (KD) did not differ between control and MSG, indicating that affinity is not affected by obesity induced by MSG. The maximum number of binding sites (Bmax) obtained in MSG subjects was lower than that obtained from control rats, indicating a decrease in the expression of total mAChRs. Immunoprecipitation assays reveal a decrease in the expression of M1 subtype of MSG when compared with control rats (M2 to M5 subtypes did not differ between control and MSG). We also observed that MSG promotes a disruption of the spatial working memory which was accompanied by a decrease in the M1 mAChR subtype in rat hippocampus, thus suggesting deleterious long-term effects besides the obesity. In conclusion, these findings provide new insights into how obesity can influence spatial learning and memory that is hippocampal-dependent. The data suggest that the M1 mAChR subtype protein expression is a potential therapeutic target.