Efeitos farmacológicos de 6-((4-fluorofenil) selanil)-9H-purina, uma promissora alternativa terapêutica em modelos experimentais de doença de Alzheimer e suas comorbidades

Abstract

Alzheimer's disease (AD) is a gradual and debilitating neurodegenerative disorder associated with several comorbidities, including anxiety and pain. Experimental studies have been looking for therapeutic alternatives that can act on the multiple aspects of this complex pathology, among them, the compounds derived from selenium, which are important in this search. Thus, the aim of the present study was to investigate the possible pharmacological effect of 6-((4-fluorophenyl) selanyl)-9H-purine (FSP) in experimental AD models in male Swiss mice. First, the binding affinity of FSP with the enzyme acetylcholinesterase (AChE) was investigated by molecular docking analysis and it was observed that FSP interacted with residues of the active site of AChE. The first AD model studied was induced by streptozotocin (STZ). Mice were treated with FSP (1 mg/kg, intragastrically (i.g.)) 30 minutes before induction with STZ (2μl of 2.5 mg/ml solution, intracerebroventricular (i.c.v.)). The treatment with the compound was carried out daily until the 10th day of the experimental protocol. Anxiety was assessed in the elevated plus-maze test and memory impairment was assessed in the Y-maze, object recognition (OR) and inhibitory avoidance tests. FSP mitigated the anxiety induction and memory impairment caused by STZ. Subsequently, the cholinergic system and Na+/K+-ATPase enzyme were investigated. FSP protected against cholinergic system dysfunction and Na+ /K+ -ATPase impairment. FSP (300 mg/kg, i.g.) did not modify the evaluated toxicological parameters. Injection of beta amyloid peptide (Aβ) (fragment 25-35) was used as the second AD model. Mice were treated with FSP (1 mg/kg, i.g.), 30 minutes before induction with Aβ (3 nmol/3 μl /per site, i.c.v.). Treatment with the compound was carried out daily until the 15th day of the experimental protocol. In this study, the effect of FSP was investigated against Aβinduced impairment of memory and hypernociception, which were evaluated in the OR task and in the Von-Frey test (VFT), respectively. FSP attenuated Aβ-induced impairment of memory and nociception sensitivity. A neuroinflammatory process was observed in the cerebral cortex and hippocampus of mice that were induced by Aβ, with an increase in expression of nuclear factor-κB (NF-κB) and cytokines. FSP decreased the expression of NF-κB in the hippocampus, and reduced proinflammatory cytokines in the cerebral cortex and hippocampus. Furthermore, βA increased the levels of oxidants and lipid peroxidation in the cerebral cortex and hippocampus, as well as decreased the expression of heme oxygenase-1 (HO-1) and peroxiredoxin-1 (Prx1) in the hippocampus. FSP protected against oxidative damage, decreasing oxidant levels, lipid peroxidation and increasing HO-1 and Prx1 expressions in the mouse hippocampus. Thus, it prevented the activation of nuclear factor erythroid 2-related factor in the Aβ-induced mouse hippocampus. In conclusion, FSP presents itself as a therapeutic alternative for AD, as it is capable of acting on multiple targets involved in this pathology.