Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain
ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD
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The highly toxic organophosphorus compound VX O-ethyl S-2-diisopropylaminoethylmethylphosphonate 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 C57BL6 mouse brain following repeated exposure 1day 3 5 days week 3 2 weeks to sublethal doses of VX 0.2 LD50 and 0.4 LD50. 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 LD50 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. Key Words neurotrophins BDNF organophosphorus compounds chemical warfare nerve agents VX mice.
- Chemical, Biological and Radiological Warfare