Apoptosis or programmed cell death is

Apoptosis or programmed cell death is a function of biochemical mechanisms, which are energy-dependent. It is considered to be a vital component of many processes such as normal cell cycle, immune mechanism, atrophy, embryonic development and toxin-induced cell death (Elmore, 2007). In addition, apoptosis is a key factor in growth and development regulation. It is a process that progresses from early development to adult stages in response to disease development and homeostasis of different stimuli in many different systems (Ulukaya et al., 2011, Felix et al., 2014). Apoptosis also occurs as a defense mechanism against xenobiotics and disease (Sulukan et al., 2017). Acetylcholine (ACh) acts as a neurotransmitter of the cholinergic system and plays an important role in many basic functions. Therefore Acetylcholinesterase (AChE) is an enzyme that plays an active role in the nervous system (Lionetto et al., 2013). Acetylcholinesterase is also an important factor in determining the effects of environmental pollutants on fish (Yen et al., 2011). Acetylcholinesterase is termination of impulse transmission by hydrolysis of the neurotransmitter prostaglandin endoperoxide synthase (Colovic et al., 2013). As pesticides affect non-target organisms in the aquatic environment, fish are important as bio indicators. Zebrafish is similar to mammals in terms of genetic, physiological and fertility. Zebrafish is also used as a model organism since it is easy to follow the embryonic developmental process (Schlueter et al., 2007).
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Introduction Despite of more than fifty years of research poisoning by the organophosphorus (OP) nerve agent soman remains a major therapeutic challenge (Eyer and Worek, 2007). Soman is an extremely potent inhibitor of acetylcholinesterase (AChE) but more important soman-inhibited AChE underlies a deleterious post-inhibitory reaction, i.e. dealkylation of the pinacolyl residue, resulting in an “aged” phosphonylated AChE which cannot be reactivated by oximes (Worek et al., 2004). The half-time of aging of soman-inhibited human AChE is in the range of ∼2min (Berry and Davies, 1966) thus reducing the window of opportunity for a successful reactivation by oximes substantially (Luo et al., 2007). However, studies with guinea pigs and rats demonstrated a therapeutic effect of oximes, primarily HI-6, in soman poisoning ex vivo and in vivo (Smith et al., 1981, Wolthuis et al., 1981, Grubic and Tomazic, 1989, Hamilton and Lundy, 1989, Lundy et al., 1992). Such species differences may be attributed to the differential aging velocity between human and animal AChE. In fact, kinetic studies with rat and guinea pig erythrocyte AChE resulted in aging half-times of ∼8min thus being some four times longer compared to human AChE (Talbot et al., 1988). Hence, testing of oximes in soman poisoning with standard animal models, i.e. oxime administration either before or immediately after soman challenge may result in a sufficient reactivation of soman-inhibited AChE in rats and guinea pigs but does by no means reflect the situation in human soman poisoning. Unfortunately, standard protocols for therapeutic animal studies generally do not include the repeated measurement of AChE activity and thus do not provide a clear evidence for reactivation of soman-inhibited AChE in vivo. A proper analysis of such species differences is of utmost importance for the extrapolation of data from therapeutic animal experiments to humans and for the assessment of the potential therapeutic effect of oximes in human soman poisoning. In order to get more insight and a basis for the extrapolation of animal data to humans, we designed a kinetic in vitro study using a well-established dynamic model with continuous, online determination of AChE activity, which was applied previously for the detailed analysis of interactions of erythrocyte, brain and muscle AChE from different species with OP, oximes and carbamates (Eckert et al., 2007, Herkert et al., 2010, Herkert et al., 2011b, Herkert et al., 2012). This model allows to simulate to some extent the in vivo situation in order to unravel the species dependent kinetic interactions between human and guinea pig AChE, soman and the oximes HI-6 and MMB-4, which are the candidate compounds to supplement or even replace the established oximes obidoxime and 2-PAM (Worek and Thiermann, 2013).