Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition

FEBS Letters

Hashimoto, Ryota¹  Lee, Min Soo²  Jeong, Mi Ra¹  Fujimaki, Koichiro¹  Ren, Ming¹  Chuang, De-Maw¹  Senatorov, Vladimir V¹ 

[1] Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bldg. 10, Rm. 4C-206, 10 Center Dr MSC 1363, Bethesda, MD 20892-1363, USA;Department of Psychiatry, College of Medicine, Korea University, Seoul 136-701, South Korea

关键词: Valproate;    Neuroprotection;    Cerebral cortical neuron;    Histone deacetylase;    Bipolar mood disorder;    Lithium;    CCNs;    cerebral cortical neurons;    HDAC;    histone deacetylase;    MTT;    3-(4;    5-dimethylthiazol-2-yl)-2;    5-diphenyltetrazolium bromide;    2M2P;    2-methyl-2-pentenoic acid;    POI-1;    propyl oligopeptidase inhibitor-1;    TSA;    trichostatin A;    VPA;    valproic acid;   

DOI  :  10.1016/S0014-5793(03)00350-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

We studied the neuroprotective effects of valproic acid (VPA), a primary mood stabilizer and anticonvulsant, in cultured rat cerebral cortical neurons (CCNs). CCNs underwent spontaneous cell death when their age increased in culture. As shown by mitochondrial activity and calcein-AM assays, treatment of CCNs with VPA starting from day 9 in vitro markedly increased viability and prolonged the life span of the cultures. The neuroprotective action of VPA was time-dependent and occurred at therapeutic levels with a maximal effect at about 0.5 mM. LiCl (1 mM) also protected CCNs from aging-induced, spontaneous cell death but less effectively. VPA-induced neuroprotection in aging CCN cultures was associated with a robust increase in histone H3 acetylation levels and the protective effect was mimicked by treatment with a histone deacetylase inhibitor, trichostatin A, but not by VPA analogs which are inactive in blocking histone deacetylase. Our results suggest a role of histone deacetylase inhibition in mediating the neuroprotective action of VPA.

【 授权许可】

Unknown