Oxidative stress status assessment of rats' brains injury following subacute exposure to K-oximes

Jacević, Vesna; Dumanović, J.; Grujić-Milanović, Jelica; Milovanović, Zoran; Amidžić, Ljiljana; Vojinović, Nataša; Nežić, Lana; Marković, Bojan; Dobričić, Vladimir; Milosavljević, Petar; Nepovimová, Eugenie; Kuča, Kamil

doi:10.1016/j.cbi.2023.110658

Cited by 2 publications

(1 citation statement)

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“…Therefore, only 1-10% of the oximes' plasma concentration is present in the brain, and their action is mostly limited to the peripheral nervous system [17]. Moreover, oximes can also be toxic at doses needed for reactivation [13] and their likely adverse toxic effects and risk-benefit ratio have to be considered in preclinical and clinical studies [18]. Since olesoxime displays excellent safety and tolerability properties and effectively crosses the BBB (reviewed in [3]), in this study we analyzed olesoxime in vitro as a ligand and potential reactivator of phosphylated AChE and BChE.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases

Kolić,

Šinko,

Jean

et al. 2024

Biomolecules

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Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.

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