Histone acetylase inhibitor trichostatin A induces acetylcholinesterase expression and protects against organophosphate exposure

Abstract

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.

BM88/Cend1 is involved in histone deacetylase inhibition‐mediated growth arrest and differentiation of neuroblastoma cells

“…TSA is an inhibitor of HDAC activity in neuroblastoma N2A cells [8–10]. It has also a cell cycle arrest and differentiation‐inducing effect on these cells ([8] and Fig.…”

“…Trichostatin A (TSA) is a potent inhibitor of histone deacetylases [2]. It inhibits growth and induces differentiation and apoptosis of mouse neuroblastoma Neuro 2A (N2A) cells [8][9][10]. We previously demonstrated that BM88/Cend1 is a neuronal-lineage specific regulator that co-ordinates cell cycle withdrawal and differentiation of neuronal progenitors [11][12][13][14][15].…”

Resveratrol induces catalytic bioscavenger paraoxonase 1 expression and protects against chemical warfare nerve agent toxicity in human cell lines

“…Transcriptional induction of bioscavengers is an innovative new strategy for combating organophosphorous chemical warfare agent exposure. We have previously shown that Trichostatin A, a histone deactylase inhibitor, has been shown to transcriptionally induce endogenous AChE expression and protect neuronal cells from OP poisoning [Curtin et al, 2005]. Induction of endogenous enzymes will minimize the production of antibodies that would otherwise be formed in response to the complex structure and post‐translational modification of the administered purified enzymes from pooled human plasma.…”

Cend1, a Story with Many Tales: From Regulation of Cell Cycle Progression/Exit of Neural Stem Cells to Brain Structure and Function

“…Histone deacetylase inhibitors (HDACIs) have been reported to arrest cell cycle and induce differentiation [64, 65]. Especially, trichostatin A (TSA), which is a potent inhibitor of histone deacetylases [65], inhibits growth and induces differentiation and apoptosis in Neuro2A cells [66–68]. In this context, it was demonstrated that TSA stimulates indirectly Cend1 promoter activity and upregulates Cend1 mRNA and protein levels in Neuro2A cells.…”