Naslov
Neurotoxic effect of potential countermeasures in case of nerve agent poisoning

Autori
T. Čadež ; Z. Kovarik

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Abstract book of 21st International ESTIV Congress / Kandarova H., Barroso J - , 2022, 187-187

ISBN
978-80-969474-7-8

Skup
21st International Congress of the European Society of Toxicology In Vitro (ESTIV 2022)

Mjesto i datum
Barcelona, Španjolska, 21.11.2022. - 25.11.2022

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
cholinesterase, OP poisoning, oximes, antidote

Sažetak
Nerve agents (NAs), the deadliest organophosphates, act as inhibitors of cholinesterase enzymes that are vital in cholinergic system. Phosphylation of acetylcholinesterase (AChE), pivotal enzyme in hydrolysis of neurotransmitter acetylcholine, and its related enzyme butyrylcholinesterase (BChE) leads to cholinergic crisis that could ultimately result in death. Medical countermeasures include compounds, containing oxime group with ability for nucleophilic reactivation of phosphylated cholinesterase, that until now have shown limited potency in reactivation of inhibited AChE in central nervous system (CNS). With that purpose, in previous studies we have designed and defined several pyridinium oxime with high potency in reactivation of inhibited BChE that can act as protector of AChE in CNS. Now through a combination of in silico, in vitro, ex vivo results we want to demonstrate a feasible approach to develop safe oxime-assisted bioscavenger of NAs based on the efficient reactivation of BChE. Selected oximes have shown to be most prominent reactivators of BChE inhibited with nerve agent cyclosarin through their overall kinetic reactivation rate. Tested oximes also shown no effect on viability of neuroblastoma cell upon 4- hours treatment, contrary to cyclosarin exposure. Furthermore, the cytotoxicity profiles on neural cells were determent for oxime-assisted catalytic BChE degradation of cyclosarin, where in case of post-treatment approach 50 % of neural cells had preserved, while in pre-treatment almost all of the cells have been protected. The most promising bioscavenger combination was then evaluated in ex vivo conditions of human blood resulting in up to 80% of restored phosphylated cholinesterase activity within a short time. Taken all together our findings

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija

POVEZANOST RADA