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Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI

Caitlin M Tressler1, Benjamin Wadsworth2, Samantha Carriero2,3

  • 1The Johns Hopkins University Applied Imaging Mass Spectrometry Core and Service Center, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

International Journal of Molecular Sciences
|June 19, 2024
PubMed

Insights

A new mouse model (KIKO) effectively simulates organophosphate (OP) poisoning, enabling better study of nerve agent effects and countermeasures. Researchers confirmed increased acetylcholine and detected reactivator drug in the brain, validating the model for future research.

Area of Science:

  • Neuroscience
  • Toxicology
  • Pharmacology

Background:

  • Organophosphate (OP) compounds inhibit acetylcholinesterase (AChE), leading to poisoning.
  • Existing animal models possess serum carboxylesterase, conferring resistance and complicating OP poisoning research.
  • A novel KIKO mouse strain with nonfunctional serum carboxylase and humanized AChE was developed.

Purpose of the Study:

  • To characterize the KIKO mouse as a functional model for studying OP poisoning and evaluating countermeasures.
  • To investigate the distribution of OP effects and countermeasure drugs within the brain.
  • To assess the ability of OP countermeasures to cross the blood-brain barrier.

Main Methods:

  • KIKO mice were exposed to an OP nerve agent and treated with a reactivator countermeasure.
  • Postmortem brain tissue was analyzed using Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging (MALDI-MSI).
  • Acetylcholine levels and the distribution of the reactivator drug were simultaneously imaged.

Main Results:

  • OP exposure led to increased acetylcholine levels in KIKO mouse brains, irrespective of treatment.
  • The reactivator countermeasure was detected in the brains of both exposed and unexposed animals.
  • MALDI-MSI successfully visualized the co-localization of acetylcholine and the reactivator within the brain.

Conclusions:

  • The KIKO mouse model is validated as a suitable platform for OP poisoning research and countermeasure development.
  • The study provides evidence that reactivator drugs may cross the blood-brain barrier.
  • This research advances the understanding of OP toxicology and the efficacy of therapeutic interventions.
Keywords:
2-PAMMALDI imagingatropineorganophosphatereactivator

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