Peripheral site ligand conjugation to a non-quaternary oxime enhances reactivation of nerve agent-inhibited human acetylcholinesterase

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

“…However, commonly employed pyridinium oxime reactivators, such as pralidoxime, HI-6 and obidoxime, are permanently charged and therefore show low penetration of the BBB. Consequently, for many years, it was assumed that the main therapeutic activity of oximes was via AChE reactivation in the peripheral nervous system (PNS) but not in the brain (de Koning et al 2011). However, oximes may be active in the central nervous system (CNS) because several of these compounds prevent seizures and brain damage in nerve agent-exposed animals (Shrot et al 2009).…”

Organophosphate Exposure

“…Due to their nucleophilic property, oximes can attack the covalent OP-enzyme adduct and release OP to recover functionally active ChE (Fig. Other oximes that can cross the BBB were also reported [84][85][86]. However, because of the highly charged nature of 2-PAM, it has a poor ability to cross the blood brain barrier (BBB).…”

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

“…7,9 In addition to this potential lethality of this overstimulation, of great concern also is the fact that AChE inhibition by OPs in the CNS can lead to seizures occurring from an excess of ACh-mediated activation of the excitotoxic glutamatergic pathways which can prolong seizures and thus lead to brain damage. 17,18 It has also been suggested that exposure to sub-lethal doses of OP can dramatically impact CNS mediated behavioural attributes such as decreased ability to perform tasks. 12 All the currently available oxime reactivators are quaternary oximes.…”