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Promoters and promotion of axonopathies
1Istituto di Medicina del Lavoro, Università degli Studi di Padova, via Giustiniani 2, 35128, Padova, Italy. amoretto@ux1.inipd.it
Abstract:
Promotion is the exacerbation by certain esterase inhibitors (organophosphates, organophosphinates, sulfonyl halides, carbamates and thiocarbamates) of the clinical and morphological expression of toxic and traumatic axonopathies. Promotion is believed to interfere with mechanisms of compensation/repair of the nerves. The target of promotion is unknown but there are indications that it might be similar and/or linked to neuropathy target esterase (NTE), which is the molecular target of organophosphate-induced delayed polyneuropathy (OPIDP). OPIDP is the model axonopathy used to characterize promotion. NTE is defined as the activity resistant to paraoxon (40 microM) and sensitive to mipafox (50 microM). An esterase activity sensitive to higher concentrations (1 mM) of mipafox was identified in the nervous system homogenate, and its inhibition correlated with promotion. An activity with similar characteristics was present in the soluble fraction of peripheral nerves and could be physically separated (about 60 kDa). Identification and characterization of the target of promotion might be helpful in understanding the mechanism(s) of compensation and repair of the peripheral nervous system.
Insights
Promotion exacerbates nerve damage by esterase inhibitors, potentially by interfering with nerve repair mechanisms. Researchers identified a novel esterase target linked to this promotion, aiding understanding of peripheral nervous system repair.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Promotion describes the worsening of nerve damage (axonopathies) by specific esterase inhibitors.
- This process is thought to hinder the nerves' natural compensation and repair mechanisms.
- The precise molecular target responsible for promotion remains unidentified.
Purpose of the Study:
- To identify the molecular target of promotion, which exacerbates toxic and traumatic axonopathies.
- To investigate the potential link between the promotion target and neuropathy target esterase (NTE).
- To characterize the biochemical properties of the identified target enzyme.
Main Methods:
- Utilized organophosphate-induced delayed polyneuropathy (OPIDP) as a model axonopathy.
- Characterized esterase activity in nervous system homogenates and soluble nerve fractions.
- Employed differential inhibition with paraoxon and mipafox to define enzyme characteristics.
- Physically separated the target enzyme using biochemical techniques.
Main Results:
- Identified a specific esterase activity in nervous system homogenates inhibited by higher mipafox concentrations (1 mM) that correlated with promotion.
- This activity was found in the soluble fraction of peripheral nerves.
- The enzyme was physically separated and characterized with an approximate molecular weight of 60 kDa.
Conclusions:
- A novel esterase target, distinct from the primary NTE activity, has been identified and characterized.
- Inhibition of this enzyme correlates with the promotion of axonopathies.
- Understanding this target may elucidate mechanisms of peripheral nerve repair and compensation.