Bruceine D elevates Nrf2 activation to restrain Parkinson's disease in mice through suppressing oxidative stress and inflammatory response
Bruceine D elevates Nrf2 activation to restrain Parkinson's disease in mice through suppressing oxidative stress and inflammatory response
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Bruceine D 通过抑制氧化应激和炎症反应来提高 Nrf2 激活以抑制小鼠帕金森病
DOI：
10.1016/j.bbrc.2020.03.097
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
郝延磊
中科院分区：
文献类型：
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作者：
郝延磊
帕金森病（Parkinson's disease，PD）是一种神经退行性疾病，以黑质多巴胺能神经元缺失、运动症状和认知功能障碍为特征。开发有效的PD治疗药物是必要的。在这项研究中，我们研究了布鲁斯因D（BD）在PD进展过程中的潜力。在建立PD小鼠模型后，我们发现BD明显改善小鼠的运动功能，并减轻化学诱导的SNpc区多巴胺能神经元酪氨酸羟化酶（TH）的丢失。BD处理通过抑制核因子κB（NF-κB）的活化，并伴随星形胶质细胞和小胶质细胞活性的降低，显著抑制SNpc中的神经炎症。BD还改善了MPTP攻击小鼠的抗氧化系统，如SNpc和纹状体（STR）中超氧化物歧化酶（SOD）和谷胱甘肽（GSH）的上调，以及丙二醛（MDA）的下调。BD的抗氧化作用是通过激活核因子E2相关因子2（Nrf 2）信号通路来调节的，该通路参与了Nrf 2下游信号通路如血红素加氧酶-1（HO-1）、NAD（P）H：醌氧化还原酶1（NQO 1）和谷胱甘肽半胱氨酸连接酶调节亚基（GCLM）的表达。在MPP+攻击的小鼠神经元中，BD通过改善Nrf 2介导的抗氧化系统而表现出细胞保护作用，并且通过阻断NF-κB信号的激活而消除MPP+触发的炎症反应。药代动力学参数和器官分布结果表明，BD显示出脑组织靶向功能。此外，体内和体外分析均表明BD副作用少。总的来说，这里的结果表明BD通过激活Nrf 2而有效抑制多巴胺能神经元损失和PD进展，而没有毒性。
Parkinson’s disease (PD) is neurodegenerative disease, featured by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characteristic motor symptoms and cognitive impairment. Development of effective therapeutic drugs for PD is necessary. In this study, we investigated the potential of Bruceine D (BD) during PD progression. After establishment of PD mouse models, we found that BD markedly improved the motor function of mice and alleviated chemically induced dopaminergic neuron loss of tyrosine hydroxylase (TH) in the SNpc area. BD treatments markedly repressed the neuroinflammation in SNpc by restricting nuclear factor κB (NF-κB) activation, accompanied with the reduced activity of astrocytes and microglial. BD also improved the antioxidant system in MPTP-challenged mice, as proved by the up-regulated superoxide dismutase (SOD) and glutathione (GSH), and down-regulated malondialdehyde (MDA) in SNpc and striatum (STR). The anti-oxidant effects of BD were regulated by the activation of nuclear factor E2-related factor 2 (Nrf2) signaling, contributing to the expression of Nrf2 down-streaming signals such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione cysteine ligase modulatory subunit (GCLM). In MPP+-challenged mouse neurons, BD exhibited cytoprotective effects by improving the Nrf2-meditated antioxidant system and abolished the MPP+-triggered inflammatory response through hindering the activation of the NF-κB signal. The pharmacokinetic parameters and organ distribution findings demonstrated that BD showed a brain tissue targeting function. Moreover, bothin vivoandin vitroanalysis indicated that BD had few side effects. Collectively, results here demonstrated that BD was effective for the inhibition of dopaminergic neuronal loss and PD progression by activating Nrf2 without toxicity.