Bellozi Paula Maria Quaglio, Gomes Giovanni Freitas, de Oliveira Leonardo Rossi, Olmo Isabella Guimarães, Vieira Érica Leandro Marciano, Ribeiro Fabíola Mara, Fiebich Bernd L, de Oliveira Antônio Carlos Pinheiro
Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Front Pharmacol. 2019 Nov 13;10:1345. doi: 10.3389/fphar.2019.01345. eCollection 2019.
Alzheimer's disease (AD) is a neurodegenerative disease and the main cause of dementia. Its major symptom is memory loss, which is a result of neuronal cell death, which is accompanied by neuroinflammation. Some studies indicate the overactivation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway in this disease, being, thus, a potential target for pharmacological treatment. Here, we used a transgenic mouse model of AD that expresses a mutant amyloid-β precursor protein (T41 mice) to investigate the effects of dactolisib (alternative name: NVP-BEZ235, abbreviation BEZ), a dual PI3K/mTOR inhibitor. Ten-months-old T41 animals were treated for 14 days with BEZ or vehicle oral gavage and then submitted to social memory, open field and contextual conditioned fear tests. Hippocampal slices were prepared and Aβ content, NeuN, Iba-1, CD68 and GFAP were evaluated. Tissues were further processed to evaluate cytokines levels through cytometric bead array. The treatment with BEZ (5 mg/kg) reduced social memory impairment in T41 mice. However, BEZ did not have any effect on altered Aβ levels, NeuN, or GFAP staining. The drug reduced the CD68/Iba-1 ratio in CA3 region of hippocampus. Finally, BEZ diminished IL-10 levels in T41 mice. Thus, although its mechanisms are not clear, BEZ protects against memory impairment, reduces microglial activation and reestablishes IL-10 levels, revealing beneficial effects, which should be further investigated for the treatment of AD.
阿尔茨海默病（AD）是一种神经退行性疾病，也是痴呆的主要病因。其主要症状是记忆丧失，这是神经元细胞死亡的结果，且伴有神经炎症。一些研究表明，磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素作用靶点（mTOR）通路在该疾病中过度激活，因此是药物治疗的一个潜在靶点。在此，我们使用了一种表达突变淀粉样β前体蛋白的AD转基因小鼠模型（T41小鼠）来研究双PI3K/mTOR抑制剂达可替尼（别名：NVP-BEZ235，缩写BEZ）的作用。10月龄的T41动物经BEZ或溶剂口服灌胃处理14天，然后进行社会记忆、旷场和情境性条件恐惧测试。制备海马切片并评估Aβ含量、神经元核抗原（NeuN）、离子钙结合衔接分子1（Iba-1）、CD68和胶质纤维酸性蛋白（GFAP）。对组织进行进一步处理，通过细胞计数珠阵列评估细胞因子水平。BEZ（5毫克/千克）治疗减轻了T41小鼠的社会记忆损害。然而，BEZ对Aβ水平改变、NeuN或GFAP染色没有任何影响。该药物降低了海马CA3区的CD68/Iba-1比值。最后，BEZ降低了T41小鼠的白细胞介素10（IL-10）水平。因此，尽管其机制尚不清楚，但BEZ可预防记忆损害，减少小胶质细胞激活并恢复IL-10水平，显示出有益效果，应进一步研究其在AD治疗中的作用。
