半合成异连翘素GSK-3β抑制剂通过AKT/GSK-3β/Nrf2通路在大鼠嗜铬细胞瘤细胞PC12和东莨菪碱诱导的AD模型小鼠中抗氧化和改善认知能力

IF 4.6 2区 医学 Q1 NEUROSCIENCES
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引用次数: 0

摘要

背景:阿尔茨海默病(AD)是一种神经退行性疾病,以进行性认知功能障碍为特征。虽然阿尔茨海默病的发病机制尚不清楚,但氧化应激被认为在其发展过程中起着主导作用。目的:在过氧化氢(H2O2)诱导的大鼠嗜铬细胞瘤PC12细胞体外实验和东莨菪碱(SCOP)诱导的AD小鼠体内实验中,研究TFGF-18通过GSK-3β途径对氧化应激的神经保护作用:方法:用H2O2(600 μM)诱导PC12细胞氧化应激,观察TFGF-18(2和8 μM)或ISO(12.5和50 μM)的作用。用 SCOP(3 毫克/千克)诱导 AD 小鼠模型,观察 TFGF-18(2 和 8 毫克/千克)、ISO(50 毫克/千克)和多奈哌齐(DNP)(3 毫克/千克)的作用。DNP是目前公认的治疗AD的药物,被用作阳性对照。流式细胞术、LDH测定、JC-1测定和Nissl染色分析了神经细胞的损伤情况。氧化应激通过检测 MDA、SOD、GPx 和 ROS 进行评估。乙酰胆碱水平以及乙酰胆碱酯酶(AChE)、胆碱酯酶(ChAT)的活性通过检测试剂盒进行检测。Bax、Bcl-2、caspase3、裂解-caspase3、p-AKT (Thr308)、AKT、p-GSK-3β (Ser9)、GSK-3β、Nrf2和HO-1以及p-CREB (Ser133)、CREB和BDNF的表达均通过Western印迹分析。莫里斯水迷宫测试分析了学习和记忆能力:结果:TFGF-18能抑制体外和体内神经元损伤、Bax caspase3和裂解caspase3的表达,并能增加Bcl-2的表达。TFGF-18 降低了 MDA 和 ROS 的水平,提高了 SOD 和 GPx 的活性。此外,TFGF-18 还能增加 p-AKT、p-GSK-3β(Ser9)、Nrf2、HO-1、p-CREB 和 BDNF 的表达,降低 H2O2 和 SCOP 的影响。同时,AKT 抑制剂 MK2206 逆转了 TFGF-18 对 AKT/GSK-3β 通路的影响。此外,TFGF-18还能重新训练胆碱能系统(ACh、ChAT和AChE)紊乱,并防止SCOP诱导的AD小鼠出现学习和记忆障碍:结论:TFGF-18可通过AKT/GSK-3β/Nrf2途径抑制氧化应激,从而防止神经细胞损伤和认知功能障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3β inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3β/Nrf2 pathway

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3β inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3β/Nrf2 pathway

Background

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits. Although the pathogenesis of AD is unclear, oxidative stress has been implicated to play a dominant role in its development. The flavonoid isoorientin (ISO) and its synthetic derivatives TFGF-18 selectively inhibit glycogen synthase kinase-3β (GSK-3β), a potential target of AD treatment.

Purpose

To investigate the neuroprotective effect of TFGF-18 against oxidative stress via the GSK-3β pathway in hydrogen peroxide (H2O2)-induced rat pheochromocytoma PC12 cells in vitro and scopolamine (SCOP)-induced AD mice in vivo.

Method

The oxidative stress of PC12 cells was induced by H2O2 (600 μM) and the effects of TFGF-18 (2 and 8 μM) or ISO (12.5 and 50 μM) were observed. The AD mouse model was induced by SCOP (3 mg/kg), and the effects of TFGF-18 (2 and 8 mg/kg), ISO (50 mg/kg), and donepezil (DNP) (3 mg/kg) were observed. DNP, a currently accepted drug for AD was used as a positive control. The neuronal cell damages were analyzed by flow cytometry, LDH assay, JC-1 assay and Nissl staining. The oxidative stress was evaluated by the detection of MDA, SOD, GPx and ROS. The level of ACh, and the activity of AChE, ChAT were detected by the assay kit. The expressions of Bax, Bcl-2, caspase3, cleaved-caspase3, p-AKT (Thr308), AKT, p-GSK-3β (Ser9), GSK-3β, Nrf2, and HO-1, as well as p-CREB (Ser133), CREB, and BDNF were analyzed by western blotting. Morris water maze test was performed to analyze learning and memory ability.

Results

TFGF-18 inhibited neuronal damage and the expressions of Bax, caspase3 and cleaved-caspase3, and increased the expression of Bcl-2 in vitro and in vivo. The level of MDA and ROS were decreased while the activities of SOD and GPx were increased by TFGF-18. Moreover, TFGF-18 increased the p-AKT, p-GSK-3β (Ser9), Nrf2, HO-1, p-CREB, and BDNF expression reduced by H2O2 and SCOP. Meanwhile, MK2206, an AKT inhibitor, reversed the effect of TFGF-18 on the AKT/GSK-3β pathway. In addition, the cholinergic system (ACh, ChAT, and AChE) disorders were retrained and the learning and memory impairments were prevented by TFGF-18 in SCOP-induced AD mice.

Conclusions

TFGF-18 protects against neuronal cell damage and cognitive impairment by inhibiting oxidative stress via AKT/GSK-3β/Nrf2 pathway.

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来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
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