Collaboration by three Chinese institutions spearheads look into new treatments by old drugs
July 2, 2012 — The cost of drug discovery and development has been skyrocketing over the past decade, yet the number of new drug approvals has fallen. Scientists are looking into new technologies and strategies to meet this challenge. Drug repositioning is one of such strategies and has been growing in importance in the last few years. On June 25, 2012, The Journal of Biological Chemistry published online the new progress of a collaborative research between Tongji University, Shanghai Institute of Materia Medica (SIMM) and Huashan Hospital about the new use of old drugs.
ARTICLE CAPSULE
The antiepileptic drug valproic acid restores T-cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis
Background: The antiepileptic drug valproic acid restores T-cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis.
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.
Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system and is one of the foremost causes of nontraumatic neurological disability in young adults. Valproic acid (VPA) is clinical used as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and less commonly, major depression. Histone deacetylases (HDACs) are the major cellular targets of VPA. By inhibiting HDACs, VPA has been reported to regulate cell proliferation, differentiation and apoptosis, and is under investigation to treat diseases involve abnormal cell proliferation, such as cancer.
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 MS.Young scientists from Tongji University (Jie Lv, Changshen Du and et al.) discovered that VPA reduces spinal cord inflammation, demyelination, and disease scores in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Further study indicated that VPA induces apoptosis in activated T cells and maintained 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 these new findings, VPA might be a safe and effective therapy for autoimmune diseases, such as MS.
This work was directed by Dr. Xin Xie, a Principle Investigator of SIMM, deputy director of the National Center for Drug Screening, and Adjunct Professor of Tongji University. Her research is mainly focused on GPCR-based drug discovery and chemical biology of stem cells. Her group recently reported that anti-asthmatic drugs targeting the CysLT1 receptor might be used to treat MS (Journal of Immunology. 2011;187(5):2336-45). The clinical samples used in this study were provided by Dr. Zhiying Wu from Huashan Hospital.
This work was supported by grants from the National Natural Science Foundation of China, Ministry of Science and Technology of China, and Shanghai Commission of Science and Technology.
Press release courtesy of the Tongji University College of Life Sciences and Technology and the Shanghai Institute of Materia Medica at the Chinese Academy of Sciences. Photo taken from the Lv et al Paper in Press.