QTC-4-MeOBnA: uma molécula racionalmente desenvolvida eficaz em modelos animais de demência e com associação à transtornos psiquiátricos

Abstract

Given the high failure rate in clinical trials evaluating drugs for the treatment of Alzheimer's Disease (AD), forms of secondary prevention have been sought, such as major depressive disorder (MDD), which is considered an important risk factor and possibly a prodromal syndrome. Among the pathological pathways that overlap between TDM and AD, the excessive production of amyloid peptide (Aβ), exacerbated inflammatory and oxidative responses, and dysfunction in neurotransmission and synaptic plasticity pathways can be highlighted. Therefore, using bioinformatics tools, the multi-target molecule, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (QTC-4-MeOBnE) was developed which has affinity with the enzymes β-secretase (BACE1), glycogen synthase kinase 3β (GSK3β) and acetylcholinesterase (AChE). In this sense, the aim of the present thesis was to evaluate the effectiveness of QTC-4-MeOBnA molecule in AD model mice and its association with TDM. Article 1 demonstrates that the administration of QTC-4-MeOBnA (0.1 and 1 mg/kg intragascatrically (ig) for 20 days) prevented the cognitive damage induced by the intracerebroventricular (i.c.v) injection of streptozotocin (STZ) (3mg/kg), by modulating the amyloidogenic cascade, GSK3β and acetylcholinesterase, without exerting nephro and hepatotoxic effects. Article 2 shows that treatment with QTC-4-MeOBnA (0.1 and 1mg/kg ig for 7 days) reversed the amnestic effect caused by scopolamine (1mg/kg intraperitoneally (ip) for 15 days), which has been attributed to modulation of the antioxidant system mediated by Nfr2 and side effects in apoptosis and neuroplasticity cascades. Furthermore, in article 3, the treatment with QTC-4-MeOBnA (1mg/Kg ig) reversed the memory impairment and neurodegenerative process induced by the i.c.v injection of STZ (3mg/kg), as a result of maintaining the integrity of the myelin sheath and stimulation of neurogenesis mediated by the Prox1/NeuroD1 and Wnt/β-catenin pathways. From the results previously obtained, article 4 shows that the administration of QTC-4-MeOBnA (1mg/kg ig, for 3 days) had the ability to reverse the depressive-like behavior and cognitive deficit induced by lipopolysaccharide (250μg ip, for 7 days), mediated by the anti-inflammatory effect through NF-κB pathway and consequent maintenance of blood brain barrier permeability, reduction of oxidative damage and microglia polarization. On the other hand, manuscript 1 evaluated the direct effect of QTC-4-MeOBnA (0.1 - 50μM) in transgenic neuronal cell models for AD and its ability to modulate the metabolism of Aβ and tau mediated by the inhibition of BACE1 and GSK3β, respectively. Also, in manuscript 2 it was found that treatment with QTC-4-MeOBnA (1mg/kg ig for 45 days) exerted an antidepressant-like effect and protected from memory damage in triple transgenic mice (3xTg) for AD, through the modulation of Aβ production and tau hyperphosphorylation, neuroinflammation and synaptic integrity. In order to explore this mechanism, manuscript 3 shows that the administration of QTC-4-MeOBnA (1mg/kg ig for 3 days) reversed neuropsychiatric alterations and cognitive decline induced by the i.c.v injection of Aβ peptide (400 pmol/mouse), by modulating the activity of the monoamine oxidase enzyme and the oxidative damage. Finally, manuscript 4 reviews the underlying effects of BACE1, GSK3β and AChE on the euroinflammatory process, metabolic/oxidative dysfunction, and synaptic plasticity and integrity, in order to discuss the results obtained throughout this project. Therefore, the evidence presented suggests the translational effect of QTC-4-MeOBnA as a promising therapeutic target for AD and for its neuropsychiatric manifestations, including MDD, which may precede cognitive and memory decline, and can be seen as a strategy of secondary prevention with the ability to slow down the neurodegenerative process.