Naslov
Novel centrally active antidote for intoxication by sarin and VX nerve agents

Autori
Zorbaz, Tamara ; Katalinić, Maja ; Zandona, Antonio ; Braiki, Anissa ; Jean, Ludovic ; Renard, Pierre Yves ; Kovarik, Zrinka

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

Izvornik
The FEBS Journal, Volume 284, Issue S1, Supplement:42nd FEBS Congress, From Molecules to Cells and Back, Jerusalem, Israel, September 10‐14, 2017 / - , 2017, 242-242

Skup
42nd FEBS CONGRESS - From molecules to cells and back

Mjesto i datum
Jeruzalem, Izrael, 10.09.2017. - 14.09.2017

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
blood-brain barier ; uncharged oxime ; nerve agent

Sažetak
Sarin and VX are some of the best known organophosphorus nerve agents (OPNA), which show their toxic effect through the irreversible inhibition of the enzymes acetylcholinesterase (AChE, E.C. 3.1.1.7.) and butyrylcholinesterase (BChE, E.C. 3.1.1.8) that normally degrade the neurotransmitter acetylcholine (ACh). This inhibition compromises normal cholinergic nerve signal transduction in the peripheral and central nervous system (PNS and CNS) synapses, leading to a cholinergic crisis with minor to medium symptoms (miosis, dyspnoea, ocular impairments, excessive secretion of body fluids, fasciculations, etc.), as well as to life- threatening impairments (respiratory failure and seizures). Survivors of attacks with these nerve agents can also experience long-term neurological impairments, e.g. cognitive and behavioural incapacitations. The antidote treatment comprises an antimuscarinic drug, an oxime reactivator of the OPNA-inhibited enzyme and an anticonvulsive drug. Standard reactivators (e.g. 2-PAM, HI-6, obidoxime) are not efficient for every OPNA, and since they have positively charged quaternary ammonium in their structures, they are ill-equipped to cross the brain-blood barrier (BBB). Novel uncharged and therefore possibly centrally active reactivators were synthesised and evaluated by in vitro and in silico methods. The in vitro reactivation assay showed that they are promising reactivators of hAChE/hBChE inhibited by VX, as well as good reactivators of hAChE inhibited by sarin. In silico- determined physicochemical parameters enabled the prediction of the amount of non-ionic species of specific antidotes at physiological pH, as well as the calculation of the CNS drug score. The cell line cytotoxicity profile showed that, at the most common therapeutic dose, they do not induce significant cell death. Induction of reactive oxygen species (ROS) production in cells was also tested to evaluate if they would have a synergistic or antagonistic effect toward one of the secondary mechanisms of neurotoxicity induced by the nerve agents (i.e. oxidative stress induction). Further in vivo BBB permeability potential and therapeutic efficacy is to be determined to conclude on the overall effectiveness of this design approach for reactivators of cholinesterases inhibited by OPNA. Acknowledgment: This work was supported by the COGITO Croatian-French bilateral grant (2015- 2016 ; PIs: Z. Kovarik and L. Jean) and by the Croatian Science Foundation (4307, PI: Z. Kovarik).

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA