Transcriptional Inducers of Acetylcholinesterase Expression as Novel Antidotes for Protection Against Chemical Warfare Agents

摘要

The biological effects of organophosphorous chemical warfare agents (CWAs) are exerted by inhibition of acetylcholinesterase (AChE), which blocks the hydrolysis of acetylcholine leading to hypercholinergy, seizures, status epilepticus, respiratory/ cardiovascular failure and death. Current investigations show that bio-scavenger therapy, using purified fetal bovine AChE and the more recently tested human BChE, is a promising treatment for protection against CWA exposure. Impediments such as the complex structure of AChEs, posttranslational modifications, poor yield, and the large amounts of serum required for purification and high-dose regimens for treatment have necessitated a need for alternative bio-scavenger approaches. We investigated the effects of transcriptional inducers to enhance the expression of AChE to achieve sufficient protection against OP poisoning. Trichostatin A (TSA), an inhibitor of histone deacetylase that de-condenses the chromatin and thereby increases the binding of transcription factors and mRNA synthesis, was evaluated for induction of AChE expression in various neuronal cell lines. Dose- response curve show that a concentration of 165 nM TSA is optimal in inducing AChE expression. In Neuro 2A cells, TSA at 165 nM increased the extra-cellular AChE level approximately 3-4-fold and intracellular enzyme 10-fold. Correlating with the AChE induction, TSA pretreatment significantly protected the cells from the cytotoxicity of organophosphate, diisopropyl flurophosphate exposure. These studies indicate that transcriptional inducers, such as TSA, up-regulate AChE, which then can bio-scavenge the organophosphates, and protect the cells from OP induced cytotoxicity, and are potential new ways to treat CWA exposure.