Organophosphorus compounds (OPs) have applications in agriculture (e.g., pesticides), industry (e.g., flame retardants), and chemical warfare (nerve agents). In high doses or chronic exposure, they can be toxic or lethal. The primary mechanism, common among all OPs, that initiates their toxic effects is the inhibition of acetylcholinesterase. In acute OP exposure, the subsequent surge of acetylcholine in cholinergic synapses causes a peripheral cholinergic crisis and status epilepticus (SE), either of which can lead to death. If death is averted without effective seizure control, long-term brain damage ensues. This review describes the mechanisms by which elevated acetylcholine can cause respiratory failure and trigger SE; the role of the amygdala in seizure initiation; the role of M1 muscarinic receptors in the early stages of SE; the neurotoxic pathways activated by SE (excitotoxicity/Ca++ overload/oxidative stress, neuroinflammation); and neurotoxic mechanisms linked to low-dose, chronic exposure (Ca++ dyshomeostasis/oxidative stress, inflammation), which do not depend on SE and do not necessarily involve acetylcholinesterase inhibition. The evidence so far indicates that brain damage from acute OP exposure is a direct result of SE, while the neurotoxic mechanisms activated by low-dose chronic exposure are independent of SE and may not be associated with acetylcholinesterase inhibition.
Keywords: acetylcholinesterase; calcium dyshomeostasis; excitotoxicity; nerve agents; neuroinflammation; neurotoxicity; organophosphates; oxidative stress; respiratory depression; status epilepticus.