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

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