Volume 1374, Issue 1 p. 52-58
Original Article

Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates

Janice E. Chambers

Corresponding Author

Janice E. Chambers

Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi

Address for correspondence: Janice E. Chambers, Center for Environmental Health Sciences, College of Veterinary Medicine, PO Box 6100, Mississippi State University, Mississippi State, MS 39762-6100. [email protected]Search for more papers by this author
Edward C. Meek

Edward C. Meek

Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi

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Howard W. Chambers

Howard W. Chambers

Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, Mississippi State, Mississippi

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First published: 06 May 2016
Citations: 28

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.