The Mood-Stabilizing Agents Lithium and Valproate RobustlIncrease the Levels of the Neuroprotective Protein bcl-2 in the CNS

Authors

  • Guang Chen,

    1. Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
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  • Wei-Zhang Zeng,

    1. Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
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  • Pei-Xiong Yuan,

    1. Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
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  • Li-Dong Huang,

    1. Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
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  • Yi-Ming Jiang,

    1. Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
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  • Zhen-Hua Zhao,

    1. Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
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  • Husseini K. Manji

    1. Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
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  • Abbreviations used : bcl-2, B cell lymphoma protein-2 ; BD, bipolar affective disorder ; DD, differential display ; FCx, frontal cortex ; Li, lithium ; PEBP, polyomavirus enhancer-binding protein ; VPA, valproate.

Address correspondence and reprint requests to Dr. H. K. Manji at Laboratory of Molecular Pathophysiology, Wayne State University School of Medicine, UHC 9B, 4201 St. Antoine Boulevard, Detroit, MI 48201, U.S.A.

Abstract

Abstract : Differential display of mRNA was used to identify concordant changes in gene expression induced by two mood-stabilizing agents, lithium and valproate (VPA). Both treatments, on chronic administration, increased mRNA levels of the transcription factor polyomavirus enhancer-binding protein (PEBP) 2β in frontal cortex (FCx). Both treatments also increased the DNA binding activity of PEBP2αβ and robustly increased the levels of bcl-2 (known to be transcriptionally regulated by PEBP2) in FCx. Immunohistochemical studies revealed a marked increase in the number of bcl-2-immunoreactive cells in layers 2 and 3 of FCx. These novel findings represent the first report of medication-induced increases in CNS bcl-2 levels and may have implications not only for mood disorders, but also for long-term treatment of various neurodegenerative disorders.

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