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J. Biol. Chem. 287 (34): 28656-28665

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: Dysregulation of T cell survival and apoptosis is the common cause of autoimmune diseases including multiple sclerosis (MS).

Results: Valproic acid (VPA) treatment restores the dysregulated apoptosis of T cells and reduces the symptoms of EAE.

Conclusion: In addition to the antiepileptic activity, VPA also regulates T cell homeostasis.

Significance: As an orally available drug, VPA might be used to treat autoimmune diseases, such as MS.

The Antiepileptic Drug Valproic Acid Restores T Cell Homeostasis and Ameliorates Pathogenesis of Experimental Autoimmune Encephalomyelitis*

Jie Lv{ddagger}§1, Changsheng Du{ddagger}1, Wei Wei{ddagger}§, Zhiying Wu, Guixian Zhao, Zhenxin Li, , and Xin Xie{ddagger}§2

From the {ddagger}Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China,
the §State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, and
the Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China

ABSTRACT Back to Top

Abstract: Maintaining a constant number and ratio of immune cells is one critical aspect of the tight regulation of immune homeostasis. Breakdown of this balance will lead to autoimmune diseases such as multiple sclerosis (MS). The antiepileptic drug valproic acid (VPA) was reported to regulate the growth, survival, and differentiation of many cells. However, its function in T cell homeostasis and MS treatment remains unknown. In this study, VPA was found to reduce spinal cord inflammation, demyelination, and disease scores in experimental autoimmune encephalomyelitis, a mouse model of MS. Further study indicated that VPA induces apoptosis in activated T cells and maintains the immune homeostasis. This effect was found to be mainly mediated by the caspase-8/caspase-3 pathway. Interestingly, this phenomenon was also confirmed in T cells from normal human subjects and MS patients. Considering the long history of clinical use and our new findings, we believe VPA might be a safe and effective therapy for autoimmune diseases, such as multiple sclerosis.

Key Words: Apoptosis • Caspase • Histone Deacetylase Inhibitors • Multiple Sclerosis • T Cell • EAE • VPA

Received for publication February 26, 2012. Revision received June 20, 2012.

FOOTNOTES Back to Top

1 These authors contributed equally to this work.

Author's Choice—Final version full access.

Creative Commons Attribution Non-Commercial License applies to Author Choice Articles

2 To whom correspondence should be addressed: 189 Guo Shou Jing Rd., Shanghai 201203, China. Tel.: 86-21-50801313, Ext. 156; Fax: 86-21-50800721; E-mail: xxie{at}mail.shcnc.ac.cn.

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