Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain

Abstract

The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish

“…In addition, ACh synthesis and degradation has to be in balance because sudden inhibition of AChE leads to paralysis and death . Previous studies have established the presence of a feedback between AChE activity and ACHE transcription − as well as other feedback mechanisms involving changes in the BCHE expression and activity of BChE − and acetycholine receptors , acting as modulators of cholinergic signaling . However, to our knowledge, there is no study in the literature testing the association between the enzyme activity and transcription levels of cholinesterases in response to the PTZ exposure in cancer cells.…”

“…38 Previous studies have established the presence of a feedback between AChE activity and ACHE transcription 39−41 as well as other feedback mechanisms involving changes in the BCHE expression and activity of BChE 42−44 and acetycholine receptors 40,45 acting as modulators of cholinergic signaling. 46 However, to our knowledge, there is no study in the literature testing the association between the enzyme activity and transcription levels of cholinesterases in response to the PTZ exposure in cancer cells. Moreover, the regulation of ACh levels is evolutionarily conserved across species, allowing in vivo studies in model organisms 47−49 with keeping in mind atypical enzymatic activities, e.g., by butyrylcholinesterases.…”