Promotion of organophosphate induced delayed polyneuropathy by certain esterase inhibitors

Organophosphate induced delayed polyneuropathy (OPIDP) is an axonopathy caused by single doses of some organophosphates (OPs). Other OPs, sulphonyl halides, carbamates, thiocarbamates and phosphinates do not cause axonopathy but elicit or intensify the clinical expression of OPIDP when given after a neuropathic OP (promotion of OPIDP). One enzymatic activity (M200) was identified by means of selective inhibitors in hen peripheral nerve crude homogenates. Promotion of OPIDP initiated with several OPs was found to correlate with inhibition of M200 when various promoters were given to hens. Most M200 is in the soluble fraction of peripheral nerves and was separated from other esterases by means of molecular exclusion chromatography. In a second series of experiments, inhibition of this fraction also correlated with promotion when induced by the same chemicals. Further ion exchange chromatography identified a protein (60 kDa MW): the inhibition of its enzymatic activity correlated with promotion in another series of in vivo experiments. Biochemical and structural analyses of this protein are underway. Several experiments indirectly suggest that promotion may be related to mechanisms of repair and/or compensation of peripheral nerves. These include the observation that promotion results in clinical expression of biochemical lesions that otherwise would be well compensated, that promotion is not specific because axonopathies of other etiology are also exaggerated, and that promoters are effective when given several days before the neuropathic insult. Moreover, developing animals are more resistant to promotion.