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Neurotoxicity Research

, Volume 13, Issue 3–4, pp 163–172 | Cite as

Protective effects ofN-Methyl-D-Aspartate receptor antagonism on VX-induced neuronal cell death in cultured rat cortical neurons

  • Yushan Wang
  • M. Tracy Weiss
  • Junfei Yin
  • Catherine C. Tenn
  • Peggy D. Elson
  • John R. Mikler
Article

Abstract

Exposure of the central nervous system to organophosphorus (OP) nerve agents induces seizures and neuronal cell death. Here we report that the OP nerve agent, VX, induces apoptoticlike cell death in cultured rat cortical neurons. The VX effects on neurons were concentrationdependent, with an IC50 of approximately 30 μM. Blockade ofN-methyl-D-aspartate receptors (NMDAR) with 50 μM D-2-amino-5-phosphonovalerate (APV) diminished 30 μM VX-induced total cell death, as assessed byalamarBlue TM assay and Hoechst staining. In contrast, neither antagonists of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) nor metabotropic glutamate receptors (mGluRs) had any effect on VX-induced neurotoxicity. VX-induced neuronal cell death could not be solely attributed to acetylcholinesterase (AChE) inhibition, since neither the reversible pharmacological cholinesterase inhibitor, physostigmine, nor the muscarinic receptor antagonist, atropine, affected VX-induced cell death. Importantly, APV was found to be therapeutically effective against VX-induced cell death up to 2 h post VX exposure. These results suggest that NMDARs, but not AMPARs or mGluRs, play important roles in VX-induced cell death in cultured rat cortical neurons. Based on their therapeutic effects, NMDAR antagonists may be beneficial in the treatment of VX-induced neurotoxicities.

Keywords

Organophosphorus nerve agents Chemical warfare agents Neuronal cell death Apoptotic-like cell death Excitatory amino acid receptors 

Abbreviations

Ach

acetylcholine

AChE

acetylcholinesterase

AMPA

α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

APV

D-2-amino-5-phosphonovalerate

CNS

Central nervous system

DCG IV

(2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropy) glycine

DHPG

(S)-3,5-dihydroxyphenylglycine

DIC

differential interference contrast

LDH

lactate dehydrogenase

MAP-2

microtubule-associated protein

MCPG

(S)- α-methyl-4-carboxyphenylglycine

mGluR

metabotropic glutamate receptor

NBQX

2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f) quinoxaline

NMDA

N-methyl-D-aspartate

OP

organophosphorus

Physos

Physostigmine

PI

Propidium iodide

PVDF

polyvinylidene difluoride

VX

O-Ethyl-S-[2(diisopropylamino)ethyl]methylphosphonothioate

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Copyright information

© Springer 2008

Authors and Affiliations

  • Yushan Wang
    • 1
    • 2
  • M. Tracy Weiss
    • 1
  • Junfei Yin
    • 1
    • 2
  • Catherine C. Tenn
    • 1
  • Peggy D. Elson
    • 1
  • John R. Mikler
    • 1
  1. 1.Defence Research & Development Canada - SuffieldMedicine HatAlbertaCanada
  2. 2.Canada West Bioscience Inc.CamroseCanada

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