Tertiary Oximes on Brain Acetylcholinesterase and Central Excitatory Effects of Nerve Agents

Abstract

Abstract. Organophosphorus nerve agents irreversibly inhibit the enzyme acetylcholinesterase (AChE), which leads to an excess of the cholinergic neurotransmitter acetylcholine in the synapses causing numerous toxic effects, including prolonged seizures and subsequent neuropathology. Current nerve agent therapies include pralidoxime (2-PAM) to reactivate inhibited AChE. The quaternary structure of this oxime does not allow it to cross the blood brain barrier (BBB) to reactivate brain AChE and to mitigate CNS toxicity. This study examined whether monoisonitrosoacetone (MINA) and N,N-diethyl-3-(2-(hydroxyimino)acetoxy) propan-1-aminium chloride (DHAP), two tertiary oximes that can penetrate the BBB, could prevent or reverse the central toxic effects of three nerve agents, sarin (GB), cyclosarin (GF), or VX, in guinea pigs. The first experiment tested whether MINA and DHAP could reactivate brain and peripheral tissue AChE inhibited by these nerve agents. Animals were challenged with a 1.0 x LD50 subcutaneous dose of a nerve agent and followed 15 min by one of 5 test doses of the oxime.

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Document Details

Document Type
Technical Report
Publication Date
Jan 01, 2012
Accession Number
ADA583112

Entities

People

  • Koenig A. Jeffrey
  • Mcdonough H. John
  • Shih Tsung-ming

Organizations

  • United States Army Medical Research Institute of Chemical Defense

Tags

Communities of Interest

  • Biomedical

DTIC Thesaurus Topics

  • Acetylcholinesterases
  • Blood Cells
  • Blood-Brain Barrier
  • Body Weight
  • Brain
  • Cells
  • Central Nervous System
  • Enzymes
  • Nerve Agents
  • Nervous System
  • Pharmacology
  • Pyridostigmine Bromide
  • Rodents
  • Skeletal Muscle
  • Spinal Cord
  • Statistical Analysis
  • Therapy

Readers

  • Neuroscience
  • Neurotoxicology