Efeito da vareniclina na prevenção do déficit de memória e aprendizado em um modelo animal de doença de Alzheimer

Abstract

The etiology of the Alzheimer's disease (AD), the most frequently diagnosed degenerative disease of the central nervous system (CNS), is not yet fully understood, but it is known that their symptoms are related to the presence of the β-amyloid peptide in the brain and its pathogenic effects in this structure induces neuronal loss, mainly in regions of the hippocampus and frontal cortex, key structures in cognitive functions associated with memory and learning. Among the various therapeutic approaches that are proposed for patients with AD, none is clearly capable of preventing or curing the disease. Among the available symptomatic treatments, we have the anticholinesterasics, which increase the availability of the neurotransmitter acetylcholine at synapses, improving cognitive performance. There are also reports indicating that the consumption of the cholinergic agonist nicotine throughout life can delay the onset of AD. Varenicline, a partial agonist of cholinergic receptors (nAChRs) α4β2 and total of α7 nAChRs, is a drug currently used to treat nicotine addiction. Considering the above, the hypothesis of this study is that varenicline can exert a neuroprotective effect, preserving memory and learning performance loss in an animal model of neurodegeneration associated with Alzheimer's disease. In order to test this hypothesis, we treated mice from postnatal day (PND) 76 with varenicline at doses of 0.5 mg/kg/day or 2 mg/kg/day, or even with nicotine at a dose 5 mg/kg/day by gavage. On PND90, the animals underwent surgery for the implantation of osmotic mini-pumps filled either with β-amyloid peptide or with a control solution (flow 0.11 µl/h for 28 days). Treatment lasted until the end of the behavioral tests on PND128. The tests used to evaluate the behaviors associated with memory and learning, locomotion, anxiety and depression were: Step down, Open Field, Object Recognition, Tail Suspension and Modified Elevated Plus Maze. The brains were collected after the behavioral tests to verify the presence of amyloid deposits and inflammatory processes. We observed that the animals that received an infusion of β-amyloid peptide and that were not treated (VEH-Aβ) presented memory and learning impairments. In the other hand, the animals that received one of the treatments (varenicline or nicotine) had its memory preserved. Behaviors associated with mobility, depression and anxiety were not affected by infusion of β-amyloid peptide. The histological analysis showed, in animals from VEH-Aβ group, the presence of Aβ peptide deposits on the wall of arteries, indicative of an amyloid angiopathy and also showed the presence of inflammatory reaction with perivascular lymphocytic infiltrate in the cortex. We also verified that the VEH-Aβ group showed features of inflammation as indicated by intense staining and typical morphology of the activated microglia. In conclusion, we demonstrated that treatment with either nicotine or varenicline can prevent memory and learning impairments in an experimental model of Alzheimer's disease.