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      Baicalein Prevents 6-Hydroxydopamine-Induced Mitochondrial Dysfunction in SH-SY5Y Cells via Inhibition of Mitochondrial Oxidation and Up-Regulation of DJ-1 Protein Expression

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          Abstract

          Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons at the substantia nigra. Mitochondrial dysfunction is involved in the mechanism of cell damage in Parkinson’s disease (PD). 6-Hydroxydopamine (6-OHDA) is a dopamine analog which specifically damages dopaminergic neurons. Baicalein has been previously reported to have potential in the treatment of PD. The purpose of the present study was to investigate the mechanism of action of baicalein against 6-OHDA injury in SH-SY5Y cells. The results showed that baicalein significantly alleviated alterations of mitochondrial redox activity and mitochondrial membrane potential induced by 6-OHDA in a dose-dependent manner in SH-SY5Y cells compared with vehicle group. Futhermore, baicalein decreased the production of ROS and upregulated the DJ-1 protein expression in SH-SY5Y cells. In addition, baicalein also inhibited ROS production and lipid peroxidation (IC 50 = 6.32 ± 0.03 μM) in rat brain mitochondia. In summary, the underlying mechanisms of baicalein against 6-OHDA-induced mitochondrial dysfunction may involve inhibition of mitochondrial oxidation and upregulation of DJ-1 protein expression.

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          Most cited references46

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          New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin.

          Traditional Chinese medicines have been recently recognized as a new source of anticancer drugs and new chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects of cancer chemotherapies however their healing mechanisms are still largely unknown. Scutellaria baicalensis is one of the most popular and multi-purpose herb used in China traditionally for treatment of inflammation, hypertension, cardiovascular diseases, and bacterial and viral infections. Accumulating evidence demonstrate that Scutellaria also possesses potent anticancer activities. The bioactive components of Scutellaria have been confirmed to be flavones. The major constituents of Scutellaria baicalensis are Wogonin, Baicalein and Baicalin. These phytochemicals are not only cytostatic but also cytotoxic to various human tumor cell lines in vitro and inhibit tumor growth in vivo. Most importantly, they show almost no or minor toxicity to normal epithelial and normal peripheral blood and myeloid cells. The antitumor functions of these flavones are largely due to their abilities to scavenge oxidative radicals, to attenuate NF-kappaB activity, to inhibit several genes important for regulation of the cell cycle, to suppress COX-2 gene expression and to prevent viral infections. The tumor-selectivity of Wogonin has recently been demonstrated to be due to its ability to differentially modulate the oxidation-reduction status of malignant vs. normal lymphocytic cells and to preferentially induce phospholipase C gamma 1, a key enzyme involved in Ca(2+) signaling, through H(2)O(2) signaling in malignant lymphocytes. This review is aimed to summarize the research results obtained since the last 20 years and to highlight the recently discovered molecular mechanisms.
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            DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.

            DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.
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              The role of mitochondria in reactive oxygen species metabolism and signaling.

              Oxidative stress is considered a major contributor to the etiology of both "normal" senescence and severe pathologies with serious public health implications. Several cellular sources, including mitochondria, are known to produce significant amounts of reactive oxygen species (ROS) that may contribute to intracellular oxidative stress. Mitochondria possess at least 10 known sites that are capable of generating ROS, but they also feature a sophisticated multilayered ROS defense system that is much less studied. This review summarizes the current knowledge about major components involved in mitochondrial ROS metabolism and factors that regulate ROS generation and removal at the level of mitochondria. An integrative systemic approach is applied to analysis of mitochondrial ROS metabolism, which is "dissected" into ROS generation, ROS emission, and ROS scavenging. The in vitro ROS-producing capacity of several mitochondrial sites is compared in the metabolic context and the role of mitochondria in ROS-dependent intracellular signaling is discussed.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                27 November 2013
                December 2013
                : 18
                : 12
                : 14726-14738
                Affiliations
                [1 ]Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University; Beijing 100191, China
                [2 ]Beijing Key Laboratory of Drug Target Identification, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
                [3 ]State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
                [4 ]Jiangsu Kanon Pharmaceutical Co., Ltd, Lianyungang 222047, China
                Author notes
                [* ]Authors to whom correspondence should be addressed; E-Mails: wangyuehua@ 123456pku.org.cn (Y.-H.W.); pxp123@ 123456bjmu.edu.cn (X.-P.P.); dugh@ 123456imm.ac.cn (G.-H.D.); Tel.: +86-10-6316-5313 (Y.-H.W.); +86-10-8280-2431 (X.-P.P.); +86-10-6316-5184 (G.-H.D.).
                Article
                molecules-18-14726
                10.3390/molecules181214726
                6270380
                24288000
                823d41c4-58a3-41f4-879c-89396e3a4899
                © 2013 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 24 September 2013
                : 18 November 2013
                : 19 November 2013
                Categories
                Article

                baicalein,parkinson’s disease,6-hydroxydopamine,sh-sy5y cells,brain mitochondria

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