The Pathogenesis of Organophosphate Polyneuropathy

Abstract

This review discusses the facts regarding organophosphate-induced delayed polyneuropathy (OPIDP) as they are related to its pathogenesis rather than being a comprehensive review of all available data. Neuropathy target esterase (NTE) is considered to be the molecular target for OPIDP which is affected by several esterase inhibitors. Such inhibitors are ranked according to their toxicological effects as follows: 1. Phosphates, phosphoroamidates, and phosphonates cause OPIDP when high amounts of NTE are inhibited. In most cases 70 to 80% inhibition is enough, whereas in others much more is required. 2. Phosphinates, carbamates, and sulfonyl halides cause either protection from or promotion of OPIDP when given before or after a neuropathic OP, respectively. Both effects are related to doses that inhibit NTE. Neuropathy is also caused by the combined treatment with a carbamate and a sulfonyl fluoride. The potency of a given NTE inhibitor to cause OPIDP is related to the chemistry of the residue left attached to NTE, in addition to its affinity for the enzyme. The capability of inhibited NTE to undergo the aging process distinguishes inhibitors with high from those with negligible or very low potency to cause OPIDP. Therefore, protection from neuropathic doses of effective OPs is obtained when NTE is mostly inhibited with nonageable inhibitors. Promotion of OPIDP is likely to involve another site besides NTE because it might occur when almost all NTE is affected. Promotion affects either progression or expression of OPIDP after the initial biochemical lesion on NTE. Since only NTE inhibitors have been proven to be promoters, it is possible that this site is made available after the initiation of OPIDP and that it may have biochemical properties indistinguishable from those of NTE of naïve birds. Age-related resistance to OPIDP also seems to be related to either progression or expression of OPIDP and/or to the different physiology of NTE at a given age. Previously reported resistance of rats to clinical OPIDP seems also to be age-dependent. The physiological function(s) of NTE is unknown, but some practical gains have been obtained from its identification, including OPIDP risk assessment and biomonitoring.