EFEITOS NEUROPROTETORES PERSISTENTES DO TRATAMENTO REPETIDO COM O ANÁLOGO TRIAZÓLICO DA GRANDISINA EM UM MODELO ANIMAL DA DOENÇA DE ALZHEIMER

Abstract

Introduction:Alzheimer’s disease (AD) results from the deposition of beta-amyloid (βA) protein in specific regions of the central nervous system, such as the cortex and hippocampus, activating inflammatory and oxidative pathways, leading to neurodegeneration. Memantine is used in moderate cases of the disease. However, it has limitations, such as loss of efficacy in more advanced cases, which is corroborated by animal models of AD. A study recently published by our research group demonstrated that the triazolic analog of grandisine (ATG) prevents cognitive impairment in animals administered with βA oligomers, through anti-inflammatory and antioxidant effects. However, to assess possible persistent effects of ATG, it will be necessary to compare the effects of this test molecule with memantine in the same model. Objective: To analyze the acute and late effects of repeated treatment with ATG in mice subjected to the AD model, using memantine as a positive control. Methodology: Three-month-old C57/Bl6 mice were used (CEUA protocol: 1.129/2020). The animals underwent stereotaxic surgery for unilateral implantation of a guide cannula in the left ventricle for intracerebroventricular (i.c.v.) injection of βA oligomers or vehicle. Twenty-four hours after surgery, repeated pharmacological treatment was initiated via intraperitoneal (i.p.) injection with ATG, vehicle, or memantine (MEM) for 14 days. The animals were divided into 4 groups according to treatment: control (i.c.v.)/vehicle (i.p.), beta-amyloid (i.c.v.)/vehicle (i.p.), beta-amyloid (i.c.v.)/MEM (i.p.), and beta-amyloid (i.c.v.)/ATG (i.p.). The object recognition test (ORT) was used to evaluate the cognitive activity of the animals and was repeated on the 8th and 16th days after βA injection. After the ORT, the animals were euthanized, and the cortex and hippocampus were dissected for molecular analyses. Results: MEM induced neuroprotective effects after 7 days of treatment, whereas the same effect was not observed after the 14th day. On the other hand, ATG prevented the recognition memory impairment in animals after 7 and 14 days of treatment, suggesting persistent neuroprotective effects. Additionally, there was a reduction in lipid peroxidation levels in the cortex and hippocampus of the animals, demonstrating the antioxidant and neuroprotective effects of the compound. Furthermore, levels of pro-inflammatory cytokines were reduced by ATG in the hippocampus, but not by MEM. Conclusion: The triazolic derivative of grandisine showed neuroprotective potential due to its antioxidant and anti-inflammatory effects, in addition to preventing persistent cognitive impairment induced by beta-amyloid injection. Keywords: Alzheimer's disease; Memantine; Grandisin, Neuroprotection; Multi-target drugs.