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Progressive Deficit of Retrograde Axonal Transport Is Associated with the Pathogenesis of Di-n-Butyl Dichlorvos Axonopathy (1987)

Moretto, Angelo ; Lotti, Marcello ; Sabri, Mohammad I. ; [et al.]

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 49 (1987), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: The induction of central-peripheral distal axonopathy in hens singly dosed with some organophosphorus (OP) compounds, such as di-n-butyl-2,2-dichlorovinyl phosphate (DBDCVP), requires greater than 80% organophosphorylation and subsequent intramolecular rearrangement (“aging”) of a protein [neuropathy target esterase (NTE)] in the axon. Suprathreshold biochemical reaction, 24 h after dosing with DBDCVP (0.75–1.00 mg/kg s.c.), is shown to be associated with progressive decrement of retrograde axonal transport in sensory and motor fibers. The maximum transport deficit (about 70% reduction) is reached 7 days after DBDCVP, prior to the appearance of axonal degeneration and the onset of clinical signs of neuropathy (day 10–11). By contrast, phenylmethylsulfonyl fluoride (30 mg/kg s.c.), an agent that prevents the development of OP neuropathy by inhibiting NTE without the “aging” reaction, had no effect on axon transport, nerve fiber integrity, or clinical status and, when administered prior to a neurotoxic dose of DBDCVP (1.00 mg/kg s.c.), prevented DBDCVP effects. Paraoxon (0.2 mg/kg s.c.) neither inhibited NTE nor caused deficits in retrograde transport or neuropathy. Taken in concert, these studies demonstrate that induced deficits in retrograde transport are associated with the pathogenesis of OP-induced nerve-fiber degeneration and the threshold-initiating mechanism thereof.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1471-4159.1987.tb01022.x

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2

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Cholinergic symptoms and Gulf War syndrome (1995)

Lotti, Marcello ; Moretto, Angelo

[s.l.] : Nature Publishing Group

Nature medicine 1 (1995), S. 1225-1226

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ISSN: 1546-170X

Source: Nature Archives 1869 - 2009

Topics: Biology , Medicine

Notes: [Auszug] To the editor — In the October issue of Nature Medicine, Soreq and colleagues describe a patient who is a homozygous carrier of atypical butyrylcholinesterase (BuChE), who reported unspecific symptoms during the Persian Gulf War after prophylactic treatment with pyridostig-mine1. Their ...

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1038/nm1295-1225b

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3

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Chlorpyrifos-induced delayed polyneuropathy (1991)

Capodicasa, Eugenio ; Scapellato, Maria Luisa ; Moretto, Angelo ; [et al.]

Springer

Archives of toxicology 65 (1991), S. 150-155

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ISSN: 1432-0738

Keywords: Chlorpyrifos ; Acetylcholinesterase ; Neuropathy target esterase ; A-Esterases ; Organophosphates ; Polyneuropathy

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60–90 mg/kg p.o., corresponding to 4–6 times the estimated LD50. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (〉70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5–6 days. High AChE inhibition (〉90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10–20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02034943

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4

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Interaction of methamidophos with hen and human acetylcholinesterase and neuropathy target esterase (1991)

Bertolazzi, Mariaemilia ; Caroldi, Stefano ; Moretto, Angelo ; [et al.]

Springer

Archives of toxicology 65 (1991), S. 580-585

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ISSN: 1432-0738

Keywords: Methamidophos isomers ; Acetylcholinesterase ; Neuropathy target esterase ; Man ; Hen ; Species differences

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Methamidophos causes acute cholinergic toxicity in several species, including man, and organophosphate-induced delayed polyneuropathy which has been reported in man but not in the hen. Acetylcholinesterase (AChE) and neuropathy target esterase (NTE) are thought to be the molecular targets of acute and delayed toxicity, respectively. The rate constants of inhibition (ka) and reactivation (k+3) of human and hen brain AChE and NTE by methamidophos resolved optical isomers are here reported. NTE inhibition was progressive and irreversible. Human and hen NTE ka (M−1·m−1) ford-(+) methamidophos was 88 and 59, respectively, and forl-(−) methamidophos 3.2 and 3.0, respectively. AChE spontaneously reactivates after inhibition.d-(+) methamidophos 10−3·ka (M−1·m−1) for human and hen AChE was 0.24 and 0.13; 103·k+3 (m−1) was 0.83 and 0.69, respectively,l-(−) Methamidophos 10−3·ka (M−1·m−1) for human and hen AChE was 5.7 and 2.8, whereas 103 · k+3 (m−1) was 6.50 and 1.52, respectively.l-(−)-Inhibited AChE reactivated to about 60% for human and 30% for hen enzymes, respectively.d-(+)-Inhibited AChE reactivated to about 10–20% for both species. Maximal reactivation occurred within 4–6 h when a plateau was reached. The larger and faster reactivation of human AChE inhibited in vitro byl-(−) methamidophos suggests that a corresponding effect might be possible in vivo and therefore explain, in part, the relatively higher susceptibility of man to delayed polyneuropathy induced by racemic methamidophos which occurs, however, with doses always causing severe cholinergic toxicity.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01973720

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5

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In vivo and in vitro regional differential sensitivity of neuropathy target esterase to Di-n-butyl-2,2-dichlorovinyl phosphate (1989)

Moretto, Angelo ; Lotti, Marcello ; Spencer, Peter S.

Springer

Archives of toxicology 63 (1989), S. 469-473

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ISSN: 1432-0738

Keywords: Acetylcholinesterase ; Di-n-butyl-2,2-dichlorovinyl phosphate ; Neuropathy target esterase ; Organo phosphates ; Polyneuropathy

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: 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.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00316450

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6

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The relevance of inhibitor-substrate interactions when measuring neuropathy target esterase inhibition (2000)

Moretto, Angelo ; Jokanovic, Milan ; Lotti, Marcello

Springer

Archives of toxicology 73 (2000), S. 655-660

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ISSN: 1432-0738

Keywords: Key words Inhibition ; Kinetics ; Neuropathy target esterase ; Organophosphates ; Phenylvalerate

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Neuropathy target esterase (NTE), thought to be the target for organophosphate polyneuropathy, is operationally defined as that neural phenyl valerate esterase resistant to paraoxon (40 μM) and sensitive to mipafox (50 μM; 20 min, pH 8.0, 37°C). The time course of inhibition of particulate paraoxon pretreated esterases by mipafox showed that the lines indicating the rate of inhibition did not pass through the log 100% activity when extrapolated at zero time. Slopes of inhibition of NTE were not linearly related to the concentration of mipafox. Kinetic parameters derived from Wilkinson type plots were: K a=49–199 μM, k +2=0.24–0.64 min−1 and k a=3.1–5.0 mM−1 m−1. When mipafox was removed (either by dilution or centrifugation) before the addition of phenyl valerate intercepts below 100% disappeared. We confirm that the formation of Michaelis complex between NTE and mipafox is not prevented by phenyl valerate and that inhibition proceeds after addition of phenyl valerate. We compared inhibitions obtained with experiments by using the traditional method (sequential incubation with inhibitors and phenyl valerate) to those obtained with a method where mipafox is removed before the addition of substrate. When calculating fixed-time 50% inhibitory concentrations (IC50s) of some inhibitors for NTE, the longer the hydrolysis time, the lower were the IC50s. Therefore, the inhibitory potency of certain NTE inhibitors, is accurately assessed only when calculating second-order rate constants (k a).

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002040050021

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Axotomy-induced ornithine decarboxylase activity in the mouse dorsal root ganglion is inhibited by the vinca alkaloids (1988)

Soiefer, Andrew I. ; Moretto, Angelo ; Spencer, Peter S. ; [et al.]

Springer

Neurochemical research 13 (1988), S. 1169-1173

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ISSN: 1573-6903

Keywords: Vinca Alkaloids ; axotomy ; retrograde axon transport ; ornithine decarboxylase ; dorsal root ganglia ; neurotoxicity

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Vinca alkaloids were used to study the role of retrograde axon transport (RT) in activating neuron perikaryal repair response to nerve transection. Mouse lumbar dorsal root ganglia (DRG) (L4-L6) were excised 48 hours after unilateral transection of the sciatic nerve and ornithine decarboxylase (ODC) activity determined. ODC activity in DRG ipsilateral to nerve transection was increased 10–20 fold over contralateral values. Typical ODC activities in ipsilateral and contralateral DRG samples were 6.18±1.4 and 0.31±0.09 pmol14CO2 released/h/3DRG, respectively. Systemic administration of single doses of either vincristine (1 mg/kg) or vinblastine (5 mg/kg) immediately prior to axotomy attenuated ODC induction in ipsilateral DRG by 39% and 47%, respectively. A direct inhibition of ODC activity in the DRG appears unlikely since only high concentrations of vinblastine (0.5–1.0 mM) were able to inhibit ODC activity in vitro. We suggest vinca alkaloids inhibit ODC induction as a consequence of distupting retrograde axonal transport. Interruption of this intracellular communication mechanism may be etiologically linked to the distal axon degeneration which follows repetitive exposure to vinca alkaloids and other agents that induce toxic axonal neuropathy.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00971635

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