The Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Egypt.
The Department of Anatomy, Faculty of Medicine, Cairo University, Egypt.
Steroids. 2020 Apr;156:108586. doi: 10.1016/j.steroids.2020.108586. Epub 2020 Jan 23.
The nuclear factor erythroid2-related factor2 (Nrf2), a chief transcriptional regulator of antioxidant response element (ARE), is considered a promising target for the prevention of Alzheimer's disease (AD). Vitamin D has been recognized to have a crucial role in improving AD cognitive functions. The present study was conducted to evaluate the effects of active vitamin D analogue, Maxacalcitol, on Keap1-Nrf2 signaling pathway in experimental Alzheimer's disease in rats.
The study was conducted on thirty female white albino rats divided equally into 3 groups: control group, Alzheimer group induced by Lipopolysaccharide and Alzheimer group treated with active vitamin D3 analogue, Maxacalcitol. The following parameters were assessed in rat brain tissues: Gene expression of Nrf2, Keap1 and MAF by RT-PCR, protein levels of phosphorylated MAPK-38p and ERK1/2 by Western Blot Technique, estimation of HO-1, Amyloid β, p-Tau levels and serum levels of TNFα, IL-10 and total 25-hydroxyvitamin D, serum calcium levels, GSH and MDA levels were also estimated in addition to cognitive function tests and histo-pathological examination of rat brain tissues.
In Alzheimer group, there was a significant deficit in cognition along with down-regulation of gene expression of Nrf2 and the protein levels of its downstream antioxidant effectors (HO-1 and GSH) with increased levels of the lipid peroxidation biomarker MDA. Also, there was increased neuro-inflammation as evidenced by increased levels of TNFα and decreased levels of IL-10. Moreover, there were increased amyloid β load and enhanced levels of phosphorylation of MAPK-38 and ERK1/2 leading to hyperphosphorylation of Tau protein. In addition, there were decreased serum levels of both total 25-hydroxyvitamin D and calcium. Treatment with vitamin D3 analogue, Maxacalcitol significantly improved cognitive dysfunction and histopathological picture of the brains of Alzheimer rats. Also, Vitamin D analogue significantly increased expression of Nrf2 and its downstream effectors (HO-1 and GSH), improved serum levels of total 25-hydroxyvitamin D and calcium, decreased neuro-inflammation and Amyloid β load as well as hyperphosphorylation of MAPK-38, ERK1/2 and tau proteins were also observed. Therefore, these data suggest that vitamin D analogue, Maxacalcitol could be used as a therapeutic agent in treatment of Alzheimer disease.
核因子红细胞 2 相关因子 2（Nrf2）是抗氧化反应元件（ARE）的主要转录调节因子，被认为是预防阿尔茨海默病（AD）的有前途的靶点。维生素 D 已被证实对改善 AD 认知功能具有重要作用。本研究旨在评估活性维生素 D 类似物 Maxacalcitol 对实验性 AD 大鼠 Keap1-Nrf2 信号通路的影响。
本研究共纳入 30 只雌性白化大鼠，平均分为 3 组：对照组、脂多糖诱导的 AD 组和 AD 治疗组。通过 RT-PCR 检测 Nrf2、Keap1 和 MAF 基因的表达，Western Blot 技术检测磷酸化 MAPK-38p 和 ERK1/2 蛋白水平，测定 HO-1、β-淀粉样蛋白、p-Tau 水平和 TNFα、IL-10 及总 25-羟维生素 D 水平，测定血清钙、GSH 和 MDA 水平，并进行认知功能测试和大鼠脑组织的组织病理学检查。
AD 组大鼠认知功能明显下降，Nrf2 基因表达及其下游抗氧化效应物（HO-1 和 GSH）蛋白水平下调，脂质过氧化生物标志物 MDA 水平升高。此外，神经炎症增加，表现为 TNFα 水平升高和 IL-10 水平降低。此外，β-淀粉样蛋白负荷增加，MAPK-38 和 ERK1/2 磷酸化水平升高，导致 Tau 蛋白过度磷酸化。此外，总 25-羟维生素 D 和钙的血清水平降低。维生素 D 类似物 Maxacalcitol 治疗可显著改善 AD 大鼠的认知功能障碍和脑组织的组织病理学变化。此外，维生素 D 类似物可显著增加 Nrf2 及其下游效应物（HO-1 和 GSH）的表达，改善总 25-羟维生素 D 和钙的血清水平，降低神经炎症和β-淀粉样蛋白负荷，以及 MAPK-38、ERK1/2 和 Tau 蛋白的过度磷酸化。因此，这些数据表明，维生素 D 类似物 Maxacalcitol 可作为治疗 AD 的治疗药物。
