engleski

The effects of organophosphorus compounds and novel antidotes on human neuronal cells

Lethal organophosphorus nerve agents (OPNA ; e.g. sarin, cyclosarin, tabun, soman, VX) still present a major treatment challenge. Medical practice today utilises an antimuscarinic atropine and the oxime reactivator of OPNA-inhibited main target acetylcholinesterase (AChE, EC 3.1.1.7). The approved pyridinium oximes (2-PAM, HI-6, obidoxime) are not efficient for every OPNA and they cannot cross the blood-brain barrier as they are charged. Our research was focused on several uncharged lipophilic oximes (JR595, JR585, GM508, CG193) designed to be passively transported across the blood-brain barrier and act in the central nervous system. Our primary testing in vitro showed that they can efficiently reactivate AChE inhibited by a range of OPNAs. However, little is still known about their in vivo beneficial effects that are not linked to reactivation and adverse effects that may be related to their structural characteristics. Namely, the preliminary testing showed higher chemosensitivity of the human neuronal cells (SH-SY5Y) to this kind of compounds. To get an insight into uncharged oximes, we thoroughly investigated their adverse effects on SH-SY5Y cells as the primary targets of these antidotes in humans. We studied the basic cytotoxicity of these oximes in terms of cell viability and cellular reactive oxygen species status. These two outcomes were also studied with OPNA compounds, which were applied in nanomolar concentrations in order to confirm oxidative stress, which is one of the proposed mechanisms of the neuronal damage in OP intoxication. Our results suggest that there is a thin line between beneficial and adverse effects of uncharged oximes on the cellular level. Therefore, our future studies will try to elucidate the mechanism behind the observed effects in vitro and to evaluate the toxicity of uncharged oximes in vivo. 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).

noncharged oximes ; cytotoxicity ; cell viability ; cellular ROS status

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