Neuropharmacology: Oxime antidotes for organophosphate pesticide and nerve agent poisoning

Organophosphate (OP) compounds remain a great threat for humans because they are used as pesticides or misused as chemical warfare nerve agents. Their mechanism of toxicity involves the irreversible inhibition of the acetylcholinesterase (AChE) enzyme important in the control of cholinergic neurotransmission at the periphery and in the brain. An available pharmacological treatment are oxime compounds, that are reactivators of OP-inhibited AChE. However, oximes are not equally effective for every possible OP and they cross the blood-brain barrier (BBB) poorly. Novel oximes are being designed and synthesized at a high rate and scale and their pharmacological efficiency is being addressed mostly with the in vitro reactivation assay. Nevertheless, only few newly synthesized oximes have shown comparable or better pharmacological properties than the ones developed more than 65 years ago beacuse oxime potential to act as efficient antidote in vivo depends on its pharmacokinetic and neuropharmacokinetics profile. This paper provides an overview of all the important aspects that should be accounted for in the search for a centrally active oxime. Furthermore, it lists the most important BBB oxime delivery strategies employed until now, and the available pharmacokinetic data on old and new oximes. NEUROTOXIC ORGANOPHOSPHATES N disorders include different conditions categorized as neurodegenerative, neuroinflammatory, neuropsychiatric, and other diseases, and as such represent one of the major global public health challenges that affect hundreds of millions of peoples worldwide (1). Conditions that originate at the level of the central nervous system (CNS) are difficult to treat both pharmacologically and surgically due to the specific anatomy and physiology of the nervous system. In addition, the nervous system is the target of many toxic compounds such as highly lethal synthetic organophosphorus compounds (OPs) derived from phosphorous, phosphonic, or phosphonic acid. They were primarily developed and used as pesticides; however, they turned out to be toxic for different species, including humans; therefore, many OP pesticides have been banned, e.g., parathion, dichlorvos (2, 3). The incidence of intentional/unintentional OP pesticide poisoning is about 3 million cases per year, while lethal outcomes of poisoning (about 200 000 cases) have mostly been recorded in developing or under-developed countries due to a lack of strict pesticide use regulation and proper medical care (4, 5). In addition, OPs are mostly colourless and odourless TAMARA ZORBAZ*