Promotion of organophosphate induced delayed polyneuropathy by certain esterase inhibitors

Abstract

Certain esterase inhibitors elicit or intensify the clinical expression of various insults to axons. This phenomenon was called promotion of axonopathies because these chemicals are not additive neurotoxicants nor do they interfere with the pharmacokinetics. Characterization of promotion was carried out by using organophosphate induced delayed polyneuropathy (OPIDP) as a model. The search for a physiological explanation of promotion has the following background: (1) Promotion expresses clinically the biochemical lesions which are otherwise well compensated (such as 30/40% neuropathy target esterase (NTE) inhibition by neuropathic organophosphates). (2) Promotion is not specific because axonopathies of different origin are affected. (3) Promoters are effective when given several days before the neuropathic insult. (4) Promotion is less effective in young animals as compared with adults. (5) Promotion occurs when axons, but not necessarily the cell body, are targeted by promoters. (6) Repeated dosing with a promoter failed to produce axonopathy. Based on this evidence it is suggested that promotion might interfere with a mechanism(s) of compensation and/or repair of long axons. The target of promotion of axonopathies is thought to be similar or linked to NTE which is defined as the phenyl valerate esterase activity (PVE) in nervous tissues resistant to paraoxon and sensitive to mipafox (40 and 50 μM, pH 8.0, 20 min, respectively). Mipafox (50 μM) resistant PVEs include some activity sensitive to the promoter phenylmethane sulfonylfluoride (PMSF) but no correlation was found between its inhibition and promotion. A complete titration curve of paraoxon-resistant PVEs by mipafox (0–1 mM) dissected, besides NTE (I50 about 10 μM), another PVE with an I50 of approximately 200 μM. This enzyme was present in hen brain, spinal cord and peripheral nerve, corresponding to about 10, 20 and 30% of NTE activity, respectively, and was sensitive both in vitro and in vivo to promoters and much less so to neuropathic NTE inhibitors. By means of chromatography, other workers have identified in soluble extracts of peripheral nerves two forms of mipafox-sensitive PVEs with different molecular weights and different sensitivity to mipafox. These might correspond to NTE and to the other enzyme. Inhibition in vivo of the latter also correlated with promotion.