Histone acetylase inhibitor trichostatin A induces acetylcholinesterase expression and protects against organophosphate exposure.
The biological effects of organophosphorous (OP) chemical warfare nerve agents (CWNAs) are exerted by inhibition of acetylcholinesterase (AChE), which prevents the hydrolysis of the neurotransmitter acetylcholine, leading to hypercholinergy, seizures/status epilepticus, respiratory/cardiovascular failure, and potentially death. Current investigations show that bioscavenger therapy using purified fetal bovine AChE in rodents and non-human primates and the more recently tested human butyrylcholinesterase, is a promising treatment for protection against multiple LD(50) CWNA exposures. Potential impediments, due to the complex structure of the enzyme, purification effort, resources, and cost have necessitated alternative approaches. Therefore, 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, thereby increasing the binding of transcription factors and mRNA synthesis, was evaluated for induction of AChE expression in various neuronal cell lines. Dose-response curves showed that a concentration of 333 nM TSA was optimal in inducing AChE expression. In Neuro-2A cells, TSA at 333 nM increased the extracellular AChE activity approximately 3-4 fold and intracellular enzyme activity 10-fold. Correlating with the AChE induction, TSA pre-treatment significantly protected the cells against exposure to the organophosphate diisopropylfluorophosphate, a surrogate for the chemical warfare agents soman and sarin. These studies indicate that transcriptional inducers such as TSA up-regulate AChE, which then can bioscavenge any organophosphates present, thereby protecting the cells from OP-induced cytotoxicity. In conclusion, transcriptional inducers are prospective new methods to protect against CWNA exposure.
Curtin
Bryan F
BF
Department of Biochemical Pharmacology, Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910-7500, USA.
Tetz
Lauren M
LM
Compton
Jaimee R
JR
Doctor
Bhupendra P
BP
Gordon
Richard K
RK
Nambiar
Madhusoodana P
MP
D000110:Acetylcholinesterase / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D002846:Chromatography, Affinity; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007531:Isoflurophate / Q000037:antagonists & inhibitors / Q000633:toxicity; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D010755:Organophosphates / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011342:Procainamide / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D010755:Organophosphates; D012333:RNA, Messenger; D007531:Isoflurophate; C012589:trichostatin A; D051548:Histone Acetyltransferases; D000110:Acetylcholinesterase; D011342:Procainamide