Although many different mechanisms are involved in the pathophysiology of OPP, standard therapy only targets a few of them, such as muscarinic receptor antagonists (atropine), cholinesterase reactivators (oximes) and anticonvulsants (benzodiazepines), although the results from different clinical studies are inconclusive regarding the efficacy of oximes and benzodiazepines in reducing morbidity or mortality in humans 8, 9.
Oxidative stress, with reactive oxygen and nitrogen species (ROS and RNS, respectively) generation, also plays an important role in the neuroinflammation and cellular death found in OPP 2, 7. Excessive accumulation of intracellular Ca 2+ can activate different lipases, proteases, endonucleases, kinases or phosphatases, resulting in damage to cell membranes, cytoskeleton or organelles 6. OP-evoked seizures can progress to status epilepticus and severe brain damage 4, 5. Shortly following OP poisoning, released EAAs can maintain the seizures independent of the initial cholinergic overstimulation 3. Thus, the onset of OP-induced seizures allows the release of excitatory amino acids (EAAs) such as glutamate and aspartate, which activate N-methyl-D-aspartate (NMDA) receptors, resulting in an intracellular influx of Ca 2+. Following the initial cholinergic overstimulation, a cascade of downstream events occurs that leads to secondary neuronal and muscle toxicity. The inhibition of AChE by OP compounds leads to accumulation of the neurotransmitter acetylcholine (ACh) at the cholinergic synaptic clefts, with the consequent long-term activation of the nicotinic and muscarinic ACh receptors (AChR) and overstimulation of cholinergic neurons as well as hyperexcitation and seizures 2. Thus, acute OP poisoning (OPP) is a major clinical and public health problem. In contrast, developed nations are most concerned about the potential military and terrorist use of these compounds because troops or civil populations can be exposed to not only chemical warfare agents based on these groups of compounds, such as soman, sarin, tabun and VX, but also pesticides or industrial OPs if they are used as improvised or dirty chemical weapons in asymmetric warfare or terrorism. Epidemiological studies regarding OP pesticides estimate approximately 3 million cases of acute severe poisoning and 300,000 deaths annually, most of them in developing countries of the Asia-Pacific region 1. Organophosphorus (OP) compounds are a class of acetylcholinesterase (AChE) inhibitors used as not only pesticides but also chemical warfare nerve agents. The suitability of the zebrafish larvae to in vivo high-throughput screenings of small molecule libraries makes these models a valuable tool for identifying new drugs for multifunctional drug therapy against acute organophosphorus poisoning.
Our results show that zebrafish models mimic most of the pathophysiological mechanisms behind this toxidrome in humans, including acetylcholinesterase inhibition, N-methyl-D-aspartate receptor activation and calcium dysregulation as well as inflammatory and immune responses. Here, we have generated and validated zebrafish models for mild, moderate and severe acute organophosphorus poisoning by exposing zebrafish larvae to different concentrations of the prototypic organophosphorus compound chlorpyrifos-oxon. Thus, development of more effective countermeasures against acute organophosphorus poisoning is urgently needed. Terrorist use of organophosphorus-based nerve agents and toxic industrial chemicals against civilian populations constitutes a real threat, as demonstrated by the terrorist attacks in Japan in the 1990 s or, even more recently, in the Syrian civil war.
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