Neuropathy target esterase-associated delayed neurotoxicity: a silent threat in organophosphorus poisoning

Neuropathy target esterase (NTE), localized predominantly to the endoplasmic reticulum, is highly expressed within the nervous system. Under physiological conditions, NTE functions mainly as a phospholipase B/lysophospholipase involved in phosphatidylcholine and lysophosphatidylcholine turnover, thereby maintaining phospholipid homeostasis, membrane integrity, and axonal stability. In toxicology, NTE is of particular interest as the principal molecular target in organophosphorus-induced delayed neurotoxicity (OPIDN), a syndrome that develops days to weeks after exposure to certain organophosphorus (OP) compounds. Unlike acute cholinergic toxicity caused by acetylcholinesterase inhibition, OPIDN is initiated by inhibition of NTE followed by "aging" of the enzyme-inhibitor complex, an essentially irreversible process considered critical for neuropathic outcome. The resulting loss of NTE activity disrupts phospholipid metabolism, promotes lysophospholipid accumulation, endoplasmic reticulum stress, calcium dyshomeostasis, and cytoskeletal breakdown, leading to distal axon degeneration in both the central and peripheral nervous systems. Clinically, OPIDN manifests after a latent phase with progressive weakness, sensory abnormalities, gait impairment, and in severe cases persistent spasticity or paralysis. This review summarizes the current knowledge on NTE structure, catalytic function, tissue distribution, and physiological significance, and integrates these findings with the molecular and clinical features of OPIDN. Particular attention is paid to the distinction between aging (neuropathic) and non-aging (non-neuropathic) NTE inhibitors, the structural determinants of neuropathic potential, and its clinical implications.