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Pro-2-PAM therapy for central and peripheral cholinesterases

James C Demar1, Edward D Clarkson, Ruthie H Ratcliffe

  • 1Walter Reed Army Institute of Research, Division of Regulated Activities, Department of Regulated Laboratories, Silver Spring, MD 20910-7500, United States.

Chemico-Biological Interactions
|February 17, 2010
PubMed

Insights

A new drug, pro-2-PAM, effectively treats organophosphorus (OP) poisoning by crossing the blood-brain barrier to restore central nervous system acetylcholinesterase (AChE) activity and prevent seizures. This novel therapeutic offers a promising solution for OP-induced neurotoxicity.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Toxicology

Background:

  • Organophosphorus (OP) agents are chemical warfare and terrorism threats.
  • Current OP exposure therapy uses atropine, pralidoxime chloride (2-PAM), and anticonvulsants.
  • Standard oximes like 2-PAM do not cross the blood-brain barrier (BBB), limiting central nervous system (CNS) treatment.

Purpose of the Study:

  • To synthesize and evaluate pro-2-PAM, a BBB-permeable 2-PAM derivative.
  • To assess pro-2-PAM's efficacy in preventing OP-induced seizures and neurotoxicity in the CNS.
  • To compare pro-2-PAM's effectiveness against standard 2-PAM in OP-exposed animals.

Main Methods:

  • Synthesis and evaluation of pro-2-PAM, a lipid-permeable 2-PAM derivative.
  • Assessment of pro-2-PAM's ability to enter the brain and reactivate CNS acetylcholinesterase (AChE).
  • Utilized electroencephalogram (EEG) monitoring, neurohistopathology, cholinesterase activity assays, and survivability studies in guinea pigs exposed to diisopropylfluorophosphate (DFP).

Main Results:

  • Pro-2-PAM significantly suppressed and eliminated seizures in DFP-exposed guinea pigs, unlike ineffective 2-PAM.
  • Pro-2-PAM treatment resulted in reduced neurological damage and higher CNS AChE activity compared to 2-PAM.
  • Both oximes showed similar peripheral nervous system (PNS) AChE activity in blood and diaphragm.

Conclusions:

  • Pro-2-PAM successfully crosses the BBB and is metabolized to 2-PAM within the brain.
  • Pro-2-PAM effectively prevents OP-induced seizures by restoring CNS AChE activity.
  • Pro-2-PAM represents the first non-invasive therapeutic for OP poisoning that targets CNS AChE reactivation.

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