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Neuropathy Target Esterase (neuropathy + target_esterase)
Selected AbstractsHigh-dose intravenous paraoxon exposure does not cause organophosphate-induced delayed neuropathy (OPIDN) in mini pigsJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2001G. Petroianu Abstract Organophosphorus compounds are inhibitors of serine hydrolases. Some of these compounds produce, in addition to their high acute toxicity, a more persistent effect: organophosphate-induced delayed neuropathy (OPIDN). The putative molecular entity whose inhibition is thought to be responsible for OPIDN is the neuropathy target esterase (NTE). Although in vitro NTE is resistant to paraoxon (PX), occasional case reports have associated PX with OPIDN. To assess clinically whether or not high-dose i.v. PX causes OPIDN in mini pigs, 14 mini pigs were anaesthesized, intubated and mechanically ventilated. In a first set of experiments eight pigs received 1 mg PX kg,1 body weight (BW) dissolved in alcohol. Two control animals received alcohol in a corresponding amount. After infusion of PX, survival of the animals during the acute phase of intoxication was achieved by intensive-care support, using appropriate drugs and fluids according to a pre-established protocol. The mini pigs were extubated 1036 ± 363 min later (mean ± SD). The pigs were observed prior to PX application and for 6 weeks thereafter for any abnormalities and/or signs of OPIDN, such as leg weakness, ataxia and paralysis. Observations were graded on a scale for three categories (position, motor deficiency, reaction), with a maximal cumulative score of 9. In a second set of experiments (four additional pigs) larger PX doses were used (3, 9, 27 and 81 mg kg,1 BW). After recovering from general anaesthesia/surgery, within 2 weeks all animals reached the initial score on the scale. It can be concluded that high-dose i.v. PX exposure does not induce OPIDN in mini pigs during the 6-week observation period. Copyright © 2001 John Wiley & Sons, Ltd. [source] The catalytic domain of human neuropathy target esterase mediates an organophosphate-sensitive ionic conductance across liposome membranesJOURNAL OF NEUROCHEMISTRY, Issue 2 2001Philip J. Forshaw In humans and other vertebrates, reaction of organophosphates with a neuronal membrane protein, neuropathy target esterase (NTE), initiates events which culminate in axonal degeneration. The initiation process appears to involve modification of a property of the protein distinct from its esterase activity, subsequent to formation of a negatively charged adduct with the active site serine residue. Here, we show that membrane patches from liposomes containing NEST, a recombinant hydrophobic polypeptide comprising the esterase domain of human NTE, display a transmembrane ionic conductance with both stable and high-frequency flickering components. An asymmetric current,voltage relationship suggested that ion flow was favoured in one direction relative to the membrane and its associated NEST molecules. Flow of anions was slightly favoured compared with cations. The flickering current formed a much larger proportion of the overall conductance in patches containing wild-type NEST compared with the catalytically inactive S966A mutant form of the protein. The conductance across patches containing NEST, but not those with the S966A mutant, was significantly reduced after adding neuropathic organophosphates to the bathing medium. By contrast, non-neuropathic covalent inhibitors of the catalytic activity of NEST did not reduce NEST-mediated conductance. Future work may establish whether NTE itself mediates an organophosphate-sensitive ion flux across intracellular membranes within intact cells. [source] NTE: One target protein for different toxic syndromes with distinct mechanisms?BIOESSAYS, Issue 8 2003Paul Glynn Epidemics of organophosphate-induced delayed neuropathy (OPIDN) have paralysed thousands of people. This syndrome of nerve axon degeneration is initiated by organophosphates which react with neuropathy target esterase (NTE). Dosing experiments with adult chickens raise the possibility that OPIDN is initiated by a gain-of-function mechanism. By contrast, loss of NTE function by mutation causes massive apoptosis in Drosophila brain. Now, Winrow et al. show that nte,/, mice die by mid-gestation, but nte+/, mice appear hyperactive and are more sensitive than wild-type mice to a fatal form of OP toxicity.1 Thus, different toxic syndromes may be initiated via a single target protein. BioEssays 25:742,745, 2003. © 2003 Wiley Periodicals, Inc. [source] | ||||||||||