Choline Transport and Metabolism in Soman‐or Sarin‐Intoxicated Brain

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Abstract

The metabolism and blood‐brain transport of choline (Ch) were investigated in perfused canine brain under control conditions and for 60 min after inhibition of brain cholinesterases by the organophosphorus (OP) compounds soman (pinacolylmethylphosphonofluoridate) and sarin (isopropylmethylphosphonofluoridate). Ch and acetylcholine (ACh) in blood and brain samples were analyzed using gas chromatography‐mass spectrometry methods. Net transport of Ch was determined by Ch analysis in arterial and venous samples. Unidirectional transport of [3H]Ch was determined using the indicator dilution method. During control perfusion periods of 90 min, net efflux of brain Ch occurred at a rate of 1.6 ± 0.4 nmol/g/ min, and the Ch content of the recirculated perfusate increased 10‐fold to ˜8 μM. Brain Ch content increased in proportion to the increase in perfusate Ch level, but brain ACh was unaltered. Rapid administration of soman (100 Hg) or sarin (400 μg) into the arterial perfusate after a 40‐min control period resulted in a > 10‐fold increase in ACh content in cerebral cortex, brainstem, and hippocampus. The ACh content of cerebellum increased only slightly. The Ch level in all four brain regions studied also increased two‐to fourfold above control levels. Ch efflux from brain, however, decreased to 0.2 ± 0.1 nmol/g/min during the 60 min after OP exposure. Unidirectional influx of [3H)Ch was 0.49 ± 0.07 nmol/g/min before and did not change significantly 10 or 40 min after OP exposure, thus indicating that the Ch transporter of the brain endothelial cell is not directly inhibited. Based on these results, it is proposed that (a) efflux of brain Ch occurs from the extracellular compartment, which becomes depleted when ACh breakdown is inhibited; (b) brain Ch is sequestered intracellularly; and (c) inhibition of cholinesterases by OP compounds stimulates synthesis of Ch, the source of which is not yet clear but which may involve hydrolysis of Ch‐containing brain lipids.

Original languageEnglish (US)
Pages (from-to)868-875
Number of pages8
JournalJournal of Neurochemistry
Volume50
Issue number3
DOIs
StatePublished - Mar 1988

Keywords

  • Acetylcholine
  • Blood‐brain transport.
  • Cerebral metabolism
  • Choline
  • Dog brain
  • Organophosphorus compounds

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