The Protective Role of Brain CYP2J in Parkinson’s Disease Models

Li, Yueran; Wu, Jinhua; Yu, Xuanji; Na, Shufang; Li, Ké; Yang, Zhongxue; Xie, Xianfei; Yang, Jing; Yue, Jiang

doi:10.1155/2018/2917981

Cited by 16 publications

(12 citation statements)

References 36 publications

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“…Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, affecting up to 1% of the global aged population over 60 years [1]. It is mainly characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) [2], which leads to striatal dopamine deficiency and results in motor symptoms such as postural instability, uncontrollable tremor, rigidity, and bradykinesia [3, 4]. Apart from motor symptoms, nonmotor symptoms, including autonomic dysfunction, sleep disturbances, cognitive problems, and depression, are commonly observed in PD [5].…”

Section: Introductionmentioning

confidence: 99%

Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson’s Disease In Vitro and In Vivo

Zhou

Shao

Yang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer's disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

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Section: Introductionmentioning

confidence: 99%

Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson’s Disease In Vitro and In Vivo

Zhou

Shao

Yang

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Numerous studies have reported that berberine has therapeutic potential against various neurodegenerative diseases, including Parkinson's, Alzheimer's, and Huntington's diseases [6]. Our previous studies have shown that CYP2J2 expressed in the brain plays a protective role in Parkinson's disease models [21]. We can, thus, speculate that one of the possible mechanisms of the therapeutic effects of berberine in neurodegenerative diseases may be the regulation of CYP2J2 expression in the brain through an increase in PPARα/RXRα heterodimer formation and binding to the CYP2J2 promoter.…”

Section: Discussionmentioning

confidence: 98%

“…CYP2J2 encodes a 502 amino acid protein that is primarily expressed in the heart, and, to a lesser degree, in the brain, pancreas, liver, kidney, gastrointestinal tract, and skeletal muscle [14]. Our previous data have shown that CYP2J2 expressed in the brain plays a protective role in Parkinson's disease models [21]. The neuroprotective effect of berberine in neurodegenerative diseases may be CYP2J2-dependent, possibly involving the catalysis of EET production from AA.…”

Section: Introductionmentioning

confidence: 99%

Berberine Induces <b><i>CYP2J2</i></b> Expression in Human U251 Glioma Cells via Regulation of Peroxisome Proliferator-Activated Receptor Alpha

Wang

et al. 2019

Pharmacology

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Background: Berberine is a promising natural drug that has a potential therapeutic effect on neurodegenerative diseases. Objectives: Using U251 cells in vitro, we investigated whether berberine exerts its neuroprotective effect via regulation of CYP2J2. Method: After pretreatment with increasing concentrations (1, 3, and 10 μmol/L) of berberine for 0.5 h, U251 cells were stimulated with 1 μg/mL of lipopolysaccharide (LPS). Cell viability was measured 24 h later using a CCK8 kit. mRNA and protein levels of CYP2J2 and peroxisome proliferator-activated receptor alpha (PPARα) were measured by quantitative real-time-polymerase chain reaction and western blotting, respectively, after 24 h of exposure to 1, 3, or 10 μmol/L berberine. Fluorescence immunocytochemistry was also used to evaluate PPARα protein expression after treatment of U251 cells with 10-μmol/L berberine for 24 h. Transient transfection (cotransfection with the plasmid of PPARα-and RXRα-containing) followed by luciferase and chromatin immunoprecipitation assays was used to elucidate the molecular mechanism underlying the observed effects. Results: Compared to the control, LPS-induced U251 cell death was attenuated by berberine in a dose-dependent manner. After 24 h, cell viability was found to be 52.3% (p < 0.05), 66.2% (p < 0.01), and 70.9% (p < 0.001) using 1, 3, and 10 μmol/L berberine treatment, respectively. At these concentrations, berberine increased the CYP2J2 mRNA levels by 1.31-fold (p < 0.05), 1.48-fold (p < 0.01), and 1.88-fold (p < 0.01), respectively, and increased the PPARα mRNA levels 1.17-fold (p < 0.05), 1.29-fold (p < 0.05), and 1.53-fold (p < 0.01), respectively, compared with the respective control groups. In addition, the CYP2J2 and PPARα protein level was also significantly upregulated in U251 cells by berberine (concentrations in 1, 3, and 10 μmol/L) in a dose-dependent manner, compared with the respective control groups. Further investigation indicated that berberine enhances the heterodimerization of PPARα and RXRα, which together bind to the CYP2J2 promoter to induce the expression of CYP2J2 in U251 cells. Conclusion: Upon exposure of U251 cells to berberine, CYP2J2 expression is induced as a result of PPARα stimulation, resulting in a neuroprotective effect.

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“…LPS (from Escherichia coli , serotype O55:B5, Sigma-Aldrich, St. Louis, MO, USA) dissolved in phosphate-buffered saline (PBS) was injected (10 μ g, 2 μ l) into the SNpc of the rats at a rate of 0.2 μ l/min by an automatic injector (CMA 402, CMA Microdialysis AB, Sweden) [ 18 , 19 ]. The syringe was left in situ for 5 min.…”

Section: Methodsmentioning

confidence: 99%

The Inhibition of miR-873 Provides Therapeutic Benefit in a Lipopolysaccharide-Induced Neuroinflammatory Model of Parkinson’s Disease

Xue

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background and Purpose. Alterations in cholesterol homeostasis have been reported in cell and animal models of Parkinson’s disease (PD), although there are inconsistent data about the association between serum cholesterol levels and risk of PD. Here, we investigated the effects of miR-873 on lysosomal cholesterol homeostasis and progressive dopaminergic neuron damage in a lipopolysaccharide-(LPS) induced model of PD. Experimental Approach. To evaluate the therapeutic benefit of the miR-873 sponge, rats were injected with a LV-miR-873 sponge or the control vector 3 days before the right-unilateral injection of LPS into the substantia nigra (SN) pars compacta, or 8 and 16 days after LPS injection. Normal SH-SY5Y cells or SH-SY5Y cells overexpressing α-synuclein were used to evaluate the distribution of α-synuclein and cholesterol in lysosomes and to assess the autophagic flux after miR-873 transfection or ABCA1 silencing. The inhibition of miR-873 significantly ameliorated the LPS-induced accumulation of α-synuclein and loss of dopaminergic neurons in the SN at the early stage. miR-873 mediated the inhibition of ABCA1 by LPS. miR-873 transfection or ABCA1 silencing increased the lysosomal cholesterol and α-synuclein levels, and decreased the autophagic flux. The knockdown of ABCA1 or A20, which are the downstream target genes of miR-873, exacerbated the damage to LPS-induced dopaminergic neurons. Conclusion and Implications. The results suggest that the inhibition of miR-873 may play a dual protective role by improving intracellular cholesterol homeostasis and neuroinflammation in PD. The therapeutic effects of the miR-873 sponge in PD may be due to the upregulation of ABCA1 and A20.

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The Protective Role of Brain CYP2J in Parkinson’s Disease Models

Cited by 16 publications

References 36 publications

Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson’s Disease In Vitro and In Vivo

Tetramethylpyrazine Analogue T-006 Exerts Neuroprotective Effects against 6-Hydroxydopamine-Induced Parkinson’s Disease In Vitro and In Vivo

Berberine Induces <b><i>CYP2J2</i></b> Expression in Human U251 Glioma Cells via Regulation of Peroxisome Proliferator-Activated Receptor Alpha

The Inhibition of miR-873 Provides Therapeutic Benefit in a Lipopolysaccharide-Induced Neuroinflammatory Model of Parkinson’s Disease

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