Toxicology and applied pharmacology

High doses of soman protect against organophosphorus-induced delayed polyneuropathy but tabun does not.

PMID 3341026


Organophosphorus-induced delayed polyneuropathy (OPIDP) is thought to result from organophosphorylation of neuropathy target esterase (NTE; formerly known as neurotoxic esterase), followed by an "aging" of the phosphorylated NTE. Protection against OPIDP should thus be achieved by production of an inhibited but "nonaging" NTE. Inhibited NTE produced in vitro by interaction with any of the four resolved isomers of soman aged negligibly (M. K. Johnson, D. J. Read, and H. P. Benschop, 1985a, Biochem. Pharmacol., 34, 1945-1951). Therefore both unresolved soman and the most inhibitory isomer (C(-)P(+)) were tested in adult hens for effects on NTE and for ability to produce OPIDP. With improved prophylaxis and therapy of acute intoxication, birds survived greater than 100 X LD50 of unresolved soman and did not develop OPIDP. One day after dosing, about half of brain and spinal cord NTE was in an unmodified (unaged) inhibited form; at this time eight survivors were challenged with a neuropathic dose of diisopropyl phosphorofluoridate (DFP). No neuropathy developed in four out of eight birds and mild to moderate signs were seen in the other four. Nine challenge control birds receiving DFP after solvent all developed severe neuropathy. Partial protection was seen in three out of three birds dosed prior to DFP challenge with sufficient C(-)P(+) isomer of soman (1.2 mg/kg sc) to convert about half of the spinal cord NTE to unaged inhibited form. Protection was not related to cholinergic shock. Two birds which survived out of eight pretreated with tabun (12 mg/kg sc) had about as much NTE inhibited as after soman administration but it was all in the modified (aged) inhibited form; these birds were not protected against DFP-induced neuropathy. A limited histopathologic examination showed that typical neurodegenerative lesions were seen only in birds with clear clinical neuropathy.