Ação neuroprotetora do composto ebselen e do exercício físico em modelos de doença de Alzheimer esporádica em camundongos

Abstract

Alzheimer's Disease (AD) is a neurodegenerative disease that reaches about 47 million people in the world and this prevalence is expected to increase over the next two decades. A range of evidence has shown that the pathogenesis of AD is still not completely clear; it is heterogeneous and involves multiple factors. Ebselen is an organoselenium compound, which has pharmacological properties. In fact, the neuroprotective effects of ebselen have been recognized and their multifactorial targets appear to be an advantage for prospective therapeutic strategies. In addition, regular physical exercise has several benefits, among them improvement of cognitive aspects in the elderly. Therefore, the main objective of this study was to investigate the neuroprotective action of ebselen and the strength exercise in the pathophysiology of animal models of sporadic AD (CEUA: 7372110915 - 6145050717). Initially, the results of article 1 demonstrated that ebselen inhibited, in vitro. In the animal models of sporadic AD, ebselen (50 mg / kg via i.p.) inhibited IC50 33.14 (28.93 - 37.97) μM, the G4 isoform activity of the hippocampal enzyme acetylcholinesterase (AChE) showed a neuroprotective effect on a scopolamine-induced amnesia model, protecting against these deleterious effects in object recognition and Y-Maze behavioral tests in Swiss mice. In addition, this compound inhibited AChE activity in the hippocampus of mice. These results suggest that ebselen modulated dysfunction in scopolamine-induced cholinergic neurotransmission. In article 2 the experimental protocol, repeated treatment with lower doses of ebselen (1 and 10 mg/kg via i.p.) in a model of AD induced by streptozotocin (STZ - 3 mg / kg via i.c.v.) was carried out. Ebselen treatment was effective in reversing the memory loss caused by STZ in mice, which was demonstrated in the object recognition and location tests and Y-Maze. In addition, the compound was effective in reversing all parameters of oxidative stress and protein levels of the apoptotic pathway in the Bax/Bcl-2, cleaved PARP/PARP ratios and caspase-3 levels in the hippocampus of STZ-treated mice. In the manuscript I mice were subjected to a non-pharmacological therapeutic treatment, a strength exercise program, which was carried out bin a ladder, where the animals underwent progressive force training (4 weeks). Strength exercise increased levels of neurogenic markers via BDNF/ERK-CAMK-II/CREB signaling in the hippocampus of mice, in addition to suppressing memory loss in the Morris water maze (MWM) test in a sporadic AD model. Finally, this thesis contributes to better understand the neuroprotective mechanisms involved in the action of ebselen and reinforces the hypothesis that this compound may be an interesting therapeutic alternative for the treatment of AD. Regarding strength exercise, the results help to understand the effects of strength exercise on AD.