In vivo and in vitro regional differential sensitivity of neuropathy target esterase to Di-n-butyl-2,2-dichlorovinyl phosphate

Angelo Moretto, Marcello Lotti, Peter Spencer

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Organophosphate-induced delayed polyneuropathy (OPIDP) is initiated by inhibition/aging of more than 70-75% of neuropathy target esterase (NTE). Di-n-butyl-2,2-dichlorovinyl phosphate (DBDCVP) (1 mg/kg s.c.) inhibited 96%, 86% and 83% of NTE in brain, spinal cord and peripheral nerve, respectively, and induced a typical central peripheral distal axonopathy in hens. A lower dose (0.45 mg/kg s.c.) caused 90%, 83% and 54% NTE inhibition in the same organs; by contrast, hens developed a spastic ataxia with axonal degeneration in spinal cord but not in peripheral nerve. With a dose of 0.2 mg/kg s.c., a suprathreshold inhibition of NTE was produced in brain (78%) but not in spinal cord (56%) and peripheral nerve (33%) and no morphological or clinical signs of neuropathy developed in hens. With doses up to 4.0 mg/kg s.c., acetylcholinesterase (AChE) inhibition was similar throughout the nervous system. In vitro time-course inhibition studies showed a different sensitivity to DBDCVP of NTE from peripheral nerve (ka = 5.4 × 106) relative to that from spinal cord (ka = 13.9 × 106) or brain (ka = 20.6 × 106). In vitro I50s of DBDCVP for AChE were similar in brain, spinal cord and peripheral nerve (11-17 nM). These data support the hypothesis that the critical target for initiation of OPIDP is located in the nerve fiber, possibly in the axon and also suggest that peripheral nerve NTE has a different sensitivity to DBDCVP than the brain enzyme. Moreover, they confirm data showing that the degree of NTE inhibition in brain after dosing with organophosphates may not be a good monitor for the enzyme in parts of the nervous system where axonal degeneration actually develops. Therefore, direct assay of peripheral nerve NTE yields data which closely correlate with degree of axonal degeneration.

Original languageEnglish (US)
Pages (from-to)469-473
Number of pages5
JournalArchives of Toxicology
Volume63
Issue number6
DOIs
StatePublished - Nov 1989
Externally publishedYes

Fingerprint

Peripheral Nerves
Brain
Spinal Cord
Organophosphates
Spinal Nerves
Polyneuropathies
Neurology
Peripheral Nervous System Diseases
Acetylcholinesterase
Nervous System
di-n-butyl-2,2-dichlorovinyl phosphate
neurotoxic esterase
In Vitro Techniques
Enzymes
Nerve Fibers
Axons
Assays
Aging of materials
Fibers

Keywords

  • Acetylcholinesterase
  • Di-n-butyl-2,2-dichlorovinyl phosphate
  • Neuropathy target esterase
  • Organo phosphates
  • Polyneuropathy

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

In vivo and in vitro regional differential sensitivity of neuropathy target esterase to Di-n-butyl-2,2-dichlorovinyl phosphate. / Moretto, Angelo; Lotti, Marcello; Spencer, Peter.

In: Archives of Toxicology, Vol. 63, No. 6, 11.1989, p. 469-473.

Research output: Contribution to journalArticle

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abstract = "Organophosphate-induced delayed polyneuropathy (OPIDP) is initiated by inhibition/aging of more than 70-75{\%} of neuropathy target esterase (NTE). Di-n-butyl-2,2-dichlorovinyl phosphate (DBDCVP) (1 mg/kg s.c.) inhibited 96{\%}, 86{\%} and 83{\%} of NTE in brain, spinal cord and peripheral nerve, respectively, and induced a typical central peripheral distal axonopathy in hens. A lower dose (0.45 mg/kg s.c.) caused 90{\%}, 83{\%} and 54{\%} NTE inhibition in the same organs; by contrast, hens developed a spastic ataxia with axonal degeneration in spinal cord but not in peripheral nerve. With a dose of 0.2 mg/kg s.c., a suprathreshold inhibition of NTE was produced in brain (78{\%}) but not in spinal cord (56{\%}) and peripheral nerve (33{\%}) and no morphological or clinical signs of neuropathy developed in hens. With doses up to 4.0 mg/kg s.c., acetylcholinesterase (AChE) inhibition was similar throughout the nervous system. In vitro time-course inhibition studies showed a different sensitivity to DBDCVP of NTE from peripheral nerve (ka = 5.4 × 106) relative to that from spinal cord (ka = 13.9 × 106) or brain (ka = 20.6 × 106). In vitro I50s of DBDCVP for AChE were similar in brain, spinal cord and peripheral nerve (11-17 nM). These data support the hypothesis that the critical target for initiation of OPIDP is located in the nerve fiber, possibly in the axon and also suggest that peripheral nerve NTE has a different sensitivity to DBDCVP than the brain enzyme. Moreover, they confirm data showing that the degree of NTE inhibition in brain after dosing with organophosphates may not be a good monitor for the enzyme in parts of the nervous system where axonal degeneration actually develops. Therefore, direct assay of peripheral nerve NTE yields data which closely correlate with degree of axonal degeneration.",
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