title: 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.
authors.affiliation: U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Pizarro
authors.forename: Wenling E
authors.initials: WE
authors.lastname: Chang
authors.forename: Mariama J
authors.initials: MJ
authors.lastname: Bah
authors.forename: Linnzi K M
authors.initials: LK
authors.lastname: Wright
authors.forename: George A
authors.initials: GA
authors.lastname: Saviolakis
authors.forename: Arun
authors.initials: A
authors.lastname: Alagappan
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Robison
authors.forename: Jinesh D
authors.initials: JD
authors.lastname: Shah
authors.forename: James L
authors.initials: JL
authors.lastname: Meyerhoff
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cerasoli
authors.forename: Eric G
authors.initials: EG
authors.lastname: Midboe
authors.forename: Lucille A
authors.initials: LA
authors.lastname: Lumley
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002619:Chemical Warfare Agents; D009946:Organothiophosphorus Compounds; C009680:VX-agent