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Baicalin Represses C/EBP? via Its Antioxidative Effect in Parkinson's Disease.

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the formation of intracellular Lewy bodies (LB) in the brain, which aggregates ?-synuclein (?-Syn) as the main component. The interest of flavonoids as potential neuroprotective agents is increasing due to its high efficiency and low side effects. Baicalin is one of the flavonoid compounds, which is a predominant flavonoid isolated from Scutellaria baicalensis Georgi. However, the key molecular mechanism by which Baicalin can prevent the PD pathogenesis remains unclear. In this study, we used bioinformatic assessment including Gene Ontology (GO) to elucidate the correlation between oxidative stress and PD pathogenesis. RNA-Seq methods were used to examine the global expression profiles of noncoding RNAs and found that C/EBP? expression was upregulated in PD patients compared with healthy controls. Interestingly, Baicalin could protect DA neurons against reactive oxygen species (ROS) and decreased C/EBP? and ?-synuclein expression in pLVX-Tet3G-?-synuclein SH-SY5Y cells. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model, the results revealed that treatment with Baicalin improved the PD model's behavioral performance and reduced dopaminergic neuron loss in the substantia nigra, associated with the inactivation of proinflammatory cytokines and oxidative stress. Hence, our study supported that Baicalin repressed C/EBP? via redox homeostasis, which may be an effective potential treatment for PD.

SUBMITTER: Lei K

PROVIDER: S-EPMC7261332 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Baicalin Represses C/EBPβ via Its Antioxidative Effect in Parkinson's Disease.

Lei Kecheng K Shen Yijue Y He Yijing Y Zhang Liwen L Zhang Jingxing J Tong Weifang W Xu Yichun Y Jin Lingjing L

Oxidative medicine and cellular longevity 20200521

Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the formation of intracellular Lewy bodies (LB) in the brain, which aggregates α-synuclein (α-Syn) as the main component. The interest of flavonoids as potential neuroprotective agents is increasing due to its high efficiency and low side effects. Baicalin is one of the flavonoid compounds, which is a predominant flavonoid isolated ...[more]

PMID: 32566108

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Project description:The oxidative metabolism of dopamine and consequent oxidative stress are implicated in dopaminergic neuronal loss, mediating the pathogenesis of Parkinson's disease (PD). The inducible detoxifying antioxidative enzyme Quinone oxidoreductase (NQO1) (NAD(P)H: quinone oxidoreductase 1), neuroprotective to counteract reactive oxidative species, is most prominent in the active stage of the disease and virtually absent at the end stage of the disease. However, the molecular mechanism dictating NQO1 expression oscillation remains unclear. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase. Unphosphorylatable NQO1 mutant displays more robust neuroprotective activity than WT NQO1 in suppressing reactive oxidative species and against MPTP-induced dopaminergic cell death, rescuing the motor disorders in both ?-synuclein transgenic transgenic male and female mice elicited by the neurotoxin. Thus, our findings demonstrate that blockade of Akt-mediated NQO1 degradation may ameliorate PD pathogenesis.SIGNIFICANCE STATEMENT Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with the imbalance of oxidative metabolism of dopamine. Quinone oxidoreductase (NQO1), a potent antioxidant system, its expression levels are prominently increased in the early and intermediate stages of PD and disappeared in the end-stage PD. The molecular modification behavior of NQO1 after it is upregulated by oxidative stress in the early stage of PD, however, remains unclear. This study shows that Akt binds and phosphorylates NQO1 at T128 residue and promotes its ubiquitination and degradation, and Parkin acts as an E3 ligase in this process, which affects the antioxidant capacity of NQO1. This finding provides a novel molecular mechanism for NQO1 oscillation in PD pathogenesis.

Dataset Information

Baicalin Represses C/EBP? via Its Antioxidative Effect in Parkinson's Disease.

Publications

Baicalin Represses C/EBP<i>β</i> via Its Antioxidative Effect in Parkinson's Disease.

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