O composto 2-(((3-trifluorometil)fenil(selanil)metil)-2,3-diidrobenzofurano apresenta eficácia terapêutica em um modelo de doença de Alzheimer esporádica induzido por estreptozotocina em camundongos

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by cognitive deficits and biochemical alterations. In this context, compounds with antioxidant and anti-inflammatory potential have been investigated as therapeutic strategies. This study investigated the effects of the compound 2-(((3- trifluoromethyl)phenyl(selanyl)methyl)-2,3-dihydrobenzofuran (TFSeB) in an experimental model of sporadic AD induced by central administration of streptozotocin (STZ) in male Swiss mice. The animals received STZ on days 1 and 3 of the protocol (cumulative dose: 3 mg/kg, intracerebroventricular, i.c.v.) and were subjected to treatment with TFSeB (1 and 5 mg/kg, intragastric, i.g.), memantine (positive control, 10 mg/kg, i.g.) or vehicle throughout the experiment. Behavioral, biochemical and molecular parameters were evaluated to understand the possible protective mechanisms involved. For memory analysis, the Y-maze, object recognition and passive avoidance tests were performed. Locomotor activity was assessed by the open field test. After euthanasia, brain structures (hippocampus, hypothalamus, cerebellum, and/or prefrontal cortex) were collected for the determination of oxidative stress biomarkers, including thiobarbituric acid-reactive substances (TBARS), reactive oxygen species (ROS), nitrate/nitrite (NOx) levels, and nonprotein sulfhydryl groups (NPSH), as well as the activity of the enzymes monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE). Hippocampal RTqPCR analyses were also performed to investigate the possible expression of genes associated with neurodegeneration, such as brain-derived neurotrophic factor (BDNF), pro-apoptotic BAX protein, anti-apoptotic BCL-2 protein, glycogen synthase kinase 3 beta (GSK-3β), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB), interleukin 6 (IL-6), nuclear factor related to factor erythroid 2 (NRF2), catalase (CAT), and superoxide dismutase (SOD). Furthermore, body weight, blood glucose, and biochemical markers of liver and kidney toxicity were evaluated in this model. These data were complemented by in silico analyses of the pharmacokinetics and toxicity of the compound TFSeB, as well as by an acute oral toxicity study in mice. The results of this study demonstrated that STZ administration significantly impaired the animals' memory and promoted biochemical alterations associated with oxidative stress, neuroinflammation, and neurotransmission imbalance. Oral treatment with TFSeB reversed several of the observed impairments, promoting memory restoration without compromising the animals' locomotion (results that were validated by the use of memantine) and protecting against deleterious changes ex vivo closely associated with neurodegenerative processes. The improvement in biochemical and molecular parameters by TFSeB in animals exposed to STZ suggests a protective effect of the compound, possibly mediated by the reduction of oxidative stress and neuroinflammation, in addition to modulating pathways associated with neuroplasticity. The in silico data, which suggest good bioavailability and potential penetration into the central nervous system, and the absence of acute oral toxicity in mice, combined with the absence of toxicity related to repeated exposure, reinforce its translational potential. Taken together, the main findings indicate that TFSeB exhibits promising therapeutic effects in a murine model of AD and relative safety, positioning it as a relevant candidate for future investigations aimed at developing new therapeutic approaches for AD.