Hematopoietic Effects of Valproic Acid in Mouse

Hwang, Hui Sung; Kim, Sang Eun; Oh, Chang Kyu; Park, Soo Jeong; Chung, Nak Gyun; Cho, Bin; Kim, Hack Ki; Han, Chi Wha; Jeong, Dae Chul

Abstract

PURPOSE
Valproic acid (VPA) has been used as an anticonvulsant for a long time. Recently, there are many reports on VPA activity with regards to intracellular signal transduction, including differentiation, proliferation, and apoptosis. We experienced several hematologic toxicities during the long-term use of VPA. Therefore, we investigated whether VPA has effects on short-term or long-term hematopoiesis with respect to differing concentrations. METHODS: We obtained bone marrow mononuclear cells (BMMNC) from a 5 week old female C3H/He strain mouse. The BMMNC were cultured in semi-solid media mixed with VPA according to the concentrations of colony forming unit for granulocyte-monocytes (CFU-GM). The concentrations of VPA were used as follows: 0.01 mM, 0.1 mM, 1 mM, and 10 mM (therapeutic level: 0.07~1.1 mM). We performed long-term liquid culture under VPA to compare the frequency of long-term culture initiating cells (LTC-IC) according to various VPA levels. RESULTS: The number of CFU-GM was highest with 1 mM of VPA (45.2+/-13.5), with higher therapeutic level than control (25.7+/-11.9), in 0.01 mM of VPA (26.5+/-12.1) and in 0.1 mM of VPA (26.6+/-12.2). In 10 mM of VPA, a toxic level of VPA, was the lowest at 1.6+/-1.1 (P< 0.01). In long-term culture, the frequency of LTC-IC was increased in 0.1 mM of VPA (67.7+/-16.3%), lower therapeutic level than in control (5.5+/-10.6%). In 1 mM of VPA, the high therapeutic level decreased to 81.6+/-9.3%. With toxic levels of VPA, 10 mM, there was no hematopoiesis. CONCLUSION: The VPA might enhance short-term hematopoiesis at high therapeutic levels, while preserving LTC-IC in long-term hematopoiesis under low therapeutic concentrations. Therefore, we suggest that VPA to be used within a low therapeutic level to escape from hematopoietic suppression when using VPA as long-term medication for seizure control.