Novel brain‐penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates
Abstract
Current oxime reactivators for organophosphate‐inhibited cholinesterase (ChE) do not effectively cross the blood–brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have developed novel substituted phenoxyalkyl pyridinium oximes that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2‐PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, treatment of rats with these novel oximes is associated with attenuation of seizure‐like behavior compared to rats treated with 2‐PAM, providing additional evidence that the oximes penetrate the blood–brain barrier. Further, some of the oximes provided 24‐h survival superior to 2‐PAM, and shortened the duration of seizure‐like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the conclusion that these oximes penetrate the brain.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 06, 2016
- Source ID
- 10.1111/nyas.13053
Entities
People
- Edward C. Meek
- Howard W. Chambers
- Janice E. Chambers
Organizations
- Defense Threat Reduction Agency
- Henry M. Jackson Foundation for the Advancement of Military Medicine
- Mississippi State University
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health