Title : Testing of novel brain-penetrating oxime reactivators of acetylcholinesterase inhibited by nerve agent surrogates.

Pub. Date : 2013 Mar 25

PMID : 23123249






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1 Testing of novel brain-penetrating oxime reactivators of acetylcholinesterase inhibited by nerve agent surrogates. Oximes acetylcholinesterase Rattus norvegicus
2 A critical need for combating the effects of organophosphate (OP) anticholinesterases, such as nerve agents, is the current lack of an effective oxime reactivator which can penetrate the blood-brain barrier (BBB), and therefore reactivate inhibited acetylcholinesterase (AChE) in the brain. Oximes acetylcholinesterase Rattus norvegicus
3 A critical need for combating the effects of organophosphate (OP) anticholinesterases, such as nerve agents, is the current lack of an effective oxime reactivator which can penetrate the blood-brain barrier (BBB), and therefore reactivate inhibited acetylcholinesterase (AChE) in the brain. Oximes acetylcholinesterase Rattus norvegicus
4 The oximes demonstrated a range of 14-76% reactivation of rat brain AChE in vitro. Oximes acetylcholinesterase Rattus norvegicus
5 An in vivo testing paradigm was developed in which the novel oxime was administered at the time of maximal brain AChE inhibition (about 80%) (1h) elicited by nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate). Oximes acetylcholinesterase Rattus norvegicus
6 This paradigm, with delayed administration of oxime to a time when brain AChE was starting to recover, was designed to minimize reactivation/reinhibition of peripheral AChE during the reactivation period which would decrease the availability of the surrogate for entry into the brain; this paradigm will allow proof of concept of BBB penetrability. Oximes acetylcholinesterase Rattus norvegicus