Organophosphate Chemical Nerve Agents, Oxidative Stress, and NADPH Oxidase Inhibitors: An Overview

Organophosphates (OPs) are potent anti-acetylcholinesterase compounds historically used as pesticides and exploited in chemical warfare. Exposure to OPs initiates cholinergic crisis with both peripheral and central effects such as salivation, lacrimation, urination, and defecation (SLUD), and status epilepticus (SE), a prolonged state of seizure. Standard medical countermeasures atropine, oximes, and benzodiazepines reduce mortality, control peripheral symptoms, and terminate SE. However, they do not attenuate the consequences of SE, including neurodegeneration, oxidative stress, neuroinflammation, epilepsy, and associated comorbidities such as cognitive dysfunction. SE induces excessive NADPH oxidase (NOX) synthesis and production of reactive oxygen species, which is a key driver of neurodegeneration and epilepsy. Furthermore, inhibition of NOX in SE-induced epilepsy models reduces neuroinflammation, neurodegeneration, and seizure frequency. Following OP toxicity, treatment with NOX inhibitors diapocynin and mitoapocynin reduced oxidative stress and astrocyte reactivity. This review summarizes the history and development of OPs and the current knowledge on OP toxicity, emphasizing the role of NOX, and the therapeutic potential of NOX inhibitors in treating long-term consequences of acute exposure to OPs.