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

• Published in: The Journal of biological chemistry Vol. 287; no. 34; pp. 28656 - 28665
• Main Authors: Lv, Jie, Du, Changsheng, Wei, Wei, Wu, Zhiying, Zhao, Guixian, Li, Zhenxin, Xie, Xin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.08.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Anticonvulsants - pharmacology; Apoptosis; Caspase; Caspase 3 - metabolism; Caspase 8 - metabolism; Drug Evaluation, Preclinical; EAE; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - metabolism; Female; Histone Deacetylase Inhibitors; Homeostasis - drug effects; Humans; Immunology; Male; Mice; Multiple Sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - metabolism; T Cell; T-Lymphocytes - metabolism; Valproic Acid - pharmacology; VPA; Multiple Sclerosis; T Cell; VPA; Caspase; EAE; Histone Deacetylase Inhibitors; Apoptosis
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M112.356584

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. 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.