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Innovative oximes as potential blood‐brain barrier penetrating cholinesterase reactivators
Author(s) -
Campbell Amy J,
Olson John,
MooradDoctor Deborah,
Kim Andrew,
Garcia Gregory E.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.947.2
Subject(s) - acetylcholinesterase , pralidoxime , organophosphate , chemistry , oxime , blood–brain barrier , in vivo , in vitro , pharmacology , glut1 , biochemistry , glucose transporter , medicine , enzyme , biology , neuroscience , microbiology and biotechnology , central nervous system , pesticide , agronomy , insulin
Organophosphate (OP) nerve agents are extremely toxic because they inhibit acetylcholinesterase (AChE). The US Army currently utilizes pralidoxime (2‐PAM) for the reactivation of peripheral OP‐inhibited AChE. However, 2‐PAM does not cross the blood‐brain barrier (BBB) at therapeutically relevant levels; therefore acute OP exposure can lead to status epilepticus (SE) which can cause brain damage. We propose to prevent SE by reactivating CNS AChE. Our oximes will potentially be transported across the BBB because they contain a sugar moiety, hence the terminology 'sugar‐oximes'. This sugar moiety could be recognized by the facilitative transporter GLUT1. Published data has shown that glucose‐oxime conjugates can prevent the body temperature inducing properties of OPs in mice, indicating a CNS effect. We have synthesized these previously reported, but understudied, sugar‐oximes and have developed an in vitro model for evaluating their reactivation of OP inhibited RBC‐ChE. Our results show several sugar‐oximes are good candidates for further studies, including in vivo efficacy studies and in vitro assays to show that the sugar‐oxime interacts with GLUT1. This work is supported by the Defense Threat Reduction Agency (DTRA).