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A Moretto

Publications and source records attributed to A Moretto.

At least 37 records · Page 2Linked to original sources
PubMed1996

Sulfonyl fluorides and the promotion of diisopropyl fluorophosphate neuropathy.

Phenylmethanesulfonyl fluoride (PMSF) enhances the neuropathic response when given to hens after organophosphates causing delayed polyneuropathy. This study was undertaken to ascertain whether other sulfonyl fluorides promote diisopropyl fluorophosphate (DFP) neuropathy in hens and if they inhibit neuropathy target esterase (NTE), the target for organophosphate-induced delayed polyneuropathy. Among seven sulfonyl fluoride analogs of PMSF (alkyl-, and phenylsulfonyl fluorides), only n-butanesulfonyl fluoride was found to be an NTE inhibitor in vitro at a concentration (I50 = 60 microM) similar to that of PMSF, n-Butanesulfonyl fluoride (0.2 mmol.kg-1 sc to hens) caused both NTE inhibition in nervous tissues (> 80%) and promotion of neuropathy after DFP (0.003 mmol.kg-1 sc) similar to those observed after the same molar dose of PMSF. These results confirm that, so far, all known promoters of organophosphate polyneuropathy are also NTE inhibitors.

Animals↗
PubMed1995

Organophosphate polyneuropathy and neuropathy target esterase: studies with methamidophos and its resolved optical isomers.

Methamidophos (O,S-dimethyl phosphorothioamidate) causes polyneuropathy in man and hens. However, experiments in the hen show that lower doses of methamidophos either protect from or promote the neuropathy caused by certain organophosphates. The initiation of neuropathy as well as protection from neuropathy are thought to be related to neuropathy target esterase (NTE), whereas promotion is likely to be due to interactions with another unknown target. Methamidophos is a racemate and we report studies with its resolved optical isomers, aimed at elucidating which isomer is responsible for the described effects. The time-course of acetylcholinesterase (AChE) and NTE activity in nervous tissues of hens after inhibition by single doses of either isomer showed that after D-(+) methamidophos (25 mg/kg PO) peak inhibition of both enzymes was achieved within 24 h (80-90%). However, after L-(-) methamidophos (15 mg/kg PO), peak inhibition (80-90%) was obtained within 24 h for AChE, whereas similar NTE inhibition (120 mg/kg PO) was observed only 4 days after dosing. The minimal neuropathic doses of D-(+) and L-(-) methamidophos were 60 and 120 mg/kg PO, respectively, and correlated with > 80% NTE inhibition in nervous tissues. OPIDP initiation by either isomer was slightly promoted by phenylmethanesulfonyl fluoride (120 mg/kg SC). D-(+) Methamidophos (25 mg/kg PO) partially protected from dibutyl dichlorovinyl-phosphate (DBDCVP) neuropathy (up to 0.8 mg/kg SC). This effect correlated with about 70% NTE inhibition. L-(-) Methamidophos (15 or 60 mg/kg PO) did not protect from DBDCVP neuropathy (0.2-0.8 mg/kg SC).

Animals↗
PubMed1995

Triphenylphosphite neuropathy in hens.

Single doses of triphenyl phosphite (TPP), a triester of trivalent phosphorus, cause ataxia and paralysis in hens. Characteristics of neurotoxicity were described as somewhat different from organophosphate induced delayed polyneuropathy (OPIDP), which is caused by triesters of pentavalent phosphorus. The onset of TPP neuropathy was reported to occur earlier than that of OPIDP (5-10 versus 7-14 days after dosing, respectively), and chromatolysis, neuronal necrosis and lesions in certain areas of the brain were found in TPP neuropathy only. Pretreatment with phenylmethanesulfonyl fluoride (PMSF) protects from OPIDP, but it either partially protected from effects of low doses or exacerbated those of higher doses of TPP. In order to account for these differences with OPIDP, it was suggested that TPP neuropathy results from the combination of two independent mechanisms of toxicity: typical OPIDP due to inhibition of neuropathy target esterase (NTE) plus a second neurotoxicity related with other target(s). We explored TPP neuropathy in the hen with attention to the phenomena of promotion and protection which are both caused by PMSF when given in combination with typical neuropathic OPs. When PMSF is given before neuropathic OPs it protects from OPIDP; when given afterwards it exaggerates OPIDP. The former effect is due to interactions with NTE, the latter to interactions with an unknown site. The time course of NTE reappearance after TPP (60 or 90 mg/kg i.v.) inhibition showed a longer half-life when compared to that after PMSF (30 mg/kg s.c.) (10-15 versus 4-6 days, respectively). The clinical signs of TPP neuropathy (60 or 90 mg/kg i.v.) were similar to those observed in OPIDP, appeared 7-12 days after treatment, correlated with more than 70% NTE inhibition/aging and were preceded by a reduction of retrograde axonal transport in sciatic nerve of hens. TPP (60 mg/kg i.v.) neuropathy was promoted by PMSF (120 mg/kg s.c.) given up to 12 days afterwards and was partially protected by PMSF (10-120 mg/kg s.c.) when given 24 h before TPP (60 or 90 mg/kg i.v.). The previously reported early onset of TPP neuropathy might be related to the higher dose used in those experiments and to the resulting more severe neuropathy. The lack of full protection might be explained by the slow kinetics of TPP, which would cause substantial NTE inhibition when PMSF effects on NTE had subsided. Since PMSF also affects the promotion site when given before initiation of neuropathy, the resulting neuropathy would then be due to both protection from and promotion of TPP effects by PMSF. No promotion by PMSF (120 mg/kg s.c.) was observed in TPP neuropathy (90 mg/kg i.v.) partially protected by PMSF (10-30 mg/kg s.c.). This might also be explained by the concurrent effects on NTE and on the promotion site obtained with PMSF pretreatment. We conclude that TPP neuropathy in the hen is likely to be the same as typical OPIDP. The unusual effects of combined treatment to hens with TPP and PMSF are explained by the prolonged pharmacokinetics of TPP and by the dual effect of PMSF i.e. protection from and promotion of OPIDP.

Animals↗
PubMed1995

Selective promotion by phenylmethanesulfonyl fluoride of peripheral and spinal cord neuropathies initiated by diisopropyl phosphorofluoridate in the hen.

This paper reports studies in hens showing that diisopropyl phosphorofluoridate (DFP) neuropathy is promoted by PMSF when initiated either in central (spinal cord) or peripheral nervous system. Moreover, the critical site for promotion is in peripheral nerve axons rather than in their cell bodies. Selective promotion in peripheral nerves was achieved by giving PMSF into sciatic artery monolaterally (7 mg/kg) to birds where neuropathy was initiated by DFP, either systematically (0.3 mg/kg s.c.) or intra-arterially (0.04 mg/kg in the same artery). Birds developed monolateral neuropathy in the leg where PMSF was delivered. Promotion of spinal cord neuropathy was achieved by giving PMSF (120 mg/kg s.c.) to birds where neuropathy was initiated selectively in spinal cord. This was obtained by protecting peripheral axons with intra-arterial bilateral injections of PMSF (0.55 x 2 mg/kg) followed by DFP (0.3, 0.4 or 0.7 mg/kg s.c.). The resulting syndrome was characterized by spastic ataxia.

Animals↗
PubMed1995

How mode of stimulus affects the relative contribution of elastance and hysteresivity to changes in lung tissue resistance.

Challenges with high concentrations of constrictor agonist delivered by intravenous vs. aerosol result in different modifications of the mechanical properties of lung tissues. We questioned whether low doses of a smooth muscle agonist administered via different routes (aerosol, i.v. bolus, i.v. continuous infusion) or an increase in positive end-expiratory pressure (PEEP) would result in different mechanical perturbations of lung tissues. Tracheal and alveolar pressures and flow were measured in open-chest mechanically ventilated (frequency 1 Hz, tidal volume 10 ml/kg, PEEP 4 cmH2O) rats under baseline conditions and after administration of low doses of methacholine or after increases in PEEP. We calculated lung elastance (EL), lung resistance, and tissue resistance (Rti) by fitting the equation of motion to changes in tracheal and alveolar pressures. Airway resistance and hysteresivity (eta) were derived from the above measurements. For comparable increases in Rti, the aerosol and PEEP groups showed large increases in EL with a decrease in eta, whereas the two intravenous groups showed large increases in eta with smaller increases in EL. The largest contribution of eta to the overall increase in Rti was seen in the intravenous bolus group. When induced changes in EL vs. induced changes in eta were plotted, different relationships were found for the four groups. We conclude that despite similar increases in Rti a different kind of mechanical perturbation occurred in the lung tissues that depended on the nature of the stimulus.

Aerosols↗
PubMed1995

Dynamic elastance and tissue resistance of isolated liquid-filled rat lungs.

The effect of the surface forces of the alveolar air-liquid interface on the dynamic behavior of lung tissue was investigated in five isolated liquid-filled rat lungs. The lungs were subjected to 0.04-Hz sinusoidal oscillation (1.5-ml tidal volume) at lung volume (VL) levels ranging from volume at zero pressure (V0) + 4 ml to V0 + 10 ml. Oscillations were performed at each VL after inflation of the lungs from V0. Alveolar pressure (PA) was measured with an alveolar capsule attached to the visceral pleura. Dynamic elastance (Edyn), tissue resistance (Rti), and hysteresivity [eta = Rti omega/Edyn, where omega is angular frequency (2 pi x frequency)] were computed from PA and VL changes. Edyn was 59.6 +/- 4.3 Pa/ml at V0 + 4 ml and varied little up to V0 + 7 ml. Thereafter, Edyn increased markedly with VL, reaching 102 +/- 16 Pa/ml at V0 + 10 ml. No significant difference was found between elastance computed from PA and that computed from pressure recorded at the airway opening. Rti was 35.2 +/- 3.6 Pa.s.ml-1 and exhibited a VL dependence similar to that of Edyn. As a result, eta was 0.16 and did not vary significantly in the explored VL range. We conclude that PA can be reliably measured in the liquid-filled lung by means of alveolar capsules. In the liquid-filled lung, Edyn was smaller than and eta was similar to values reported for air-filled lungs. Hence, surface tension accounts for a considerable part of elastance and Rti of the air-filled lung within the volume range of normal breathing.

Animals↗
PubMed1994

The phosphorothioic acid O-(2-chloro-2,3,3-trifluorocyclobutyl) O-ethyl S-propyl ester exacerbates organophosphate polyneuropathy without inhibition of neuropathy target esterase.

Organophosphate-induced delayed polyneuropathy (OPIDP) is thought to be initiated by a variety of neuropathy target esterase (NTE) inhibitors. However, certain inhibitors such as phenylmethanesulfonyl fluoride, phenyl N-methyl N-benzyl carbamate, and phenyl di-n-pentyl phosphinate protect from OPIDP when given to hens before organophosphorus esters. They protect from neuropathy by preventing the binding of neuropathic inhibitors to NTE catalytic site. In contrast, when such NTE inhibitors are given afterward, the resulting clinical effect is more severe. This phenomenon was called promotion of OPIDP. Promotion has been tentatively explained by the interaction of promoters with a target other than the catalytic center of NTE. However, the doses of promoters which cause the effect have, so far, been found to always be inhibitory of NTE. We report that the phosphorothioic acid O-(2-chloro-2,3,3-trifluorocyclobutyl) O-ethyl S propyl ester (KBR-2822) given to hens at doses which did not inhibit NTE (2.5 mg/kg p.o.) promoted the neuropathies initiated by either dibutyl-2,2-dichlorovinyl phosphate (DBDCVP, 0.4 mg/kg s.c., 24 hr earlier) or diisopropyl phosphorofluoridate (DFP, 0.3 mg/kg sc or 0.5 mg/kg s.c., 24 hr earlier). When given alone, DBDCVP and DFP (0.5 mg/kg) caused mild OPIDP, whereas the lower dose of DFP did not cause clinical effects. Dose-response relationships with KBR-2822 indicated that clinical effects of the combined treatments are unlikely to be additive because the compound did not cause OPIDP up to the maximum tolerated dose (10 mg/kg p.o.). Promotion also occurred when KBR-2822 (2.5 mg/kg p.o.) was given before either DBDCVP (0.4 mg/kg s.c.) or DFP (0.3 mg/kg s.c.). NTE inhibitions in the nervous tissues caused by DBDCVP or DFP were not affected by pretreatment with KBR-2822, suggesting that the delivery of neuropathic. NTE inhibitors was not modified. We conclude that KBR-2822 promotes OPIDP initiated by either DBDCVP or DFP by affecting a target other than NTE catalytic site.

Animals↗
PubMed1994

Airway and tissue behavior during induced constriction in rats: intravenous vs. aerosol administration.

The distribution of contractile agonist during intravenous (i.v.) or aerosol (AR) administration is likely to be different. We questioned whether the different pattern of distribution would result in different effects on lung tissue response. We measured tracheal and alveolar pressure in open-chest mechanically ventilated [frequency 1 Hz, tidal volume 8 ml/kg, positive end-expiratory pressure (PEEP) 3 cmH2O] rats under control conditions and after i.v. or AR administration of saline or methacholine (MCh; i.v., 50 micrograms.kg-1.min-1; AR, 256 mg/ml). We calculated lung elastance and resistances of lung, tissue, and airway by fitting the equation of motion to changes in tracheal and alveolar pressure. Lungs were then frozen in situ with liquid nitrogen (PEEP=3 cmH2O) and processed via freeze substitution. Airway constriction was assessed by measuring the ratio of airway lumen to ideally relaxed area. Tissue distortion was assessed by measuring mean linear intercept between alveolar walls (Lm), atelectasis index (ATI) derived by calculating ratio of tissue to air space, and SD of Lm and ATI. I.v. and AR MCh increased lung resistance to a similar degree. However, changes in tissue resistance and lung elastance after AR MCh were significantly greater than those after i.v. MCh, whereas the change in airway resistance was significantly less. After i.v. MCh, airway constriction was prominent and evenly distributed. After AR MCh, airway constriction was less prominent and decreased as airway size decreased. Tissue distortion, i.e., SD of Lm and ATI, was significantly greater after AR than i.v. MCh.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1994

Effect of elastase on oscillation mechanics of lung parenchymal strips.

Using isolated parenchymal strips from degassed rat lungs, we studied the contribution of the collagen-elastin network to lung tissue hysteretic behavior. Strips were suspended in an organ bath filled with Krebs solution (37 degrees C, pH 7.4) continuously bubbled with 95% O2-5% CO2. One end of the strip was attached to a force transducer and the other to a servo-controlled lever arm. Sinusoidal oscillations of 2.5% of resting length were applied at 1 Hz. Measurements were sampled under baseline conditions at different levels of stress (sigma = 10-26 g/cm). Porcine pancreatic elastase (0.05 IU.mg tissue-1.ml Krebs solution-1) was then added to the bath, and tension and length were measured continuously for 15 min at sigma = 15 g/cm. After washout, measurements were repeated at sigma = 10-26 g/cm. Elastance (E) and resistance (R) were calculated using the equation of motion. Hysteresivity (eta), the structural damping coefficient, was obtained using the following equation: eta = (R/E) pi 2f, where f is frequency. At baseline, we found that E and R were significantly dependent on sigma (P < 0.01), whereas eta was unchanged. During enzymatic digestion with elastase, there were significant decreases of tension, E, and R and no change in eta. Significant increases in E and R were found when these parameters were compared at the same sigma before and after treatment. Again, eta did not change. The constancy of eta after elastase suggests that disruption of the elastin-collagen network does not alter the coupling between elastic and dissipative processes in lung tissue.

Animals↗
PubMed1994

Airway and tissue responses to antigen challenge in sensitized brown Norway rats.

It has recently been shown in several species that lung tissue resistance increases after administration of exogenous bronchoconstrictors. This finding suggests the possibility that lung parenchymal tissues could be involved in the pathophysiology of pulmonary allergic responses. To test this hypothesis, we sensitized Brown Norway rats with ovalbumin (OA) and performed experiments in anesthetized, open-chested, mechanically ventilated (respiratory frequency [f] = 1 Hz, tidal volume [VT] = 9 ml/kg, positive end-expiratory pressure [PEEP] = 3 cm H2O) animals. We affixed alveolar capsules to the lungs to measure alveolar pressure and calculated the resistance of lung (RL), tissue (Rti), and airway (Raw) under control conditions and after aerosol administration of saline (S) (n = 10) or OA (n = 14). To assess lung morphometry during the late response, the lungs of six S and six OA animals were frozen with liquid nitrogen (PEEP = 3 cm H2O) and processed via freeze substitution. Airway constriction was assessed by measuring the ratio of the airway lumen (A) to the ideally relaxed airway (Ar). Tissue distortion was assessed by measuring the mean linear intercept between alveolar walls (Lm), an atelectasis index (ATI) derived by calculating the ratio of tissue/airspace, and the standard deviation (SD) of Lm and ATI. In the OA group, all animals demonstrated an early response (ER; RL, Rti, Raw = 183.5 +/- 7.7, 159.7 +/- 9.9, 232.5 +/- 17.2% baseline, respectively) and 11 animals showed a late response (LR; RL, Rti, Raw = 178.9 +/- 5.1, 191.3 +/- 11.5, 176.6 +/- 17.3% baseline, respectively). Neither ER nor LR were observed in the saline group.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1993

Organophosphate polyneuropathy in chicks.

Young animals are resistant to organophosphate-induced delayed neuropathy (OPIDP), although biochemical changes on Neuropathy Target Esterase (NTE) caused by neuropathic organophosphorus esters (OP) are similar to those observed in the sensitive hen. We report here that the resistance of chicks to single doses of neuropathic OPs is not absolute because ataxia was produced in 40-day-old chicks by 2,2-dichlorovinyl dibutyl phosphate (DBDCVP, 5.0 or 10.0 mg/kg s.c.) and by diisopropyl phosphorofluoridate (DFP, 2.0 mg/kg s.c.). However, the clinical picture was different from that usually seen in hens; spasticity and complete recovery being the main features. alpha-Tolyl sulphonyl fluoride (PMSF, 300 mg/kg s.c.) promoted both DBDCVP neuropathy (5.0 or 10.0 mg/kg s.c.) and non-neuropathic doses of DFP (1.5 mg/kg s.c.) or DBDCVP (1.0 mg/kg s.c.). The lowest promoting dose of PMSF given 24 hr after 1.5 mg/kg of DFP was 30 mg/kg. Higher doses had a more severe effect but no further increase of OPIDP severity was obtained with doses ranging from 90 to 300 mg/kg. PMSF (30 mg/kg) protected 40-day-old chicks from subsequent doses of neuropathic OPs even when a promoting dose of PMSF followed. At 60 days of age, chicks' resistance to OPIDP decreased because lower doses of neuropathic OPs became effective and, similarly to hens, PMSF did not fully protect from subsequent promotion. In 40-day-old chicks the threshold of NTE inhibition for OPIDP development was 95-97% (DBDCVP 5.0 mg/kg). When promotion followed initiation, the minimal effective inhibition of NTE for initiation by neuropathic OPs was about 90%. In 36-day-old chicks, PMSF (300 mg/kg) promoted OPIDP when given up to 5 days after DFP (1.5 mg/kg) when residual NTE inhibition in brain and sciatic nerve was about 40%. We conclude that chicks' resistance to OPIDP might reflect either a less effective initiation by phosphorylated NTE or a more efficient repair mechanism or both, and also that promotion is likely to involve a target other than NTE.

Age Factors↗
PubMed1993

Interactions between neuropathy target esterase and its inhibitors and the development of polyneuropathy.

This paper combines new and old data in order to offer a modified perspective of the mechanism of organophosphate-induced delayed polyneuropathy. Neuropathy target esterase (NTE) is though to be the molecular target and neuropathy to be initiated with a two-step mechanism: progressive inhibition of NTE and aging of the phosphorylated enzyme. When neuropathic organophosphates modify more than 70% of NTE in this way, neuropathy develops 2 weeks later. Other chemicals producing an inhibited NTE, which is incapable of aging, were thought to be not neuropathic. When given before a challenging dose of a neuropathic organophosphate they protect animals from neuropathy. However, recent evidence indicates that aging may not always be essential in causing neuropathy. In fact, mipafox and methamidophos as well as certain classic protective inhibitors such as carbamate and sulfonyl fluoride form an inhibited NTE which apparently does not age and yet produces neuropathy. We propose that all NTE inhibitors may have the potential to cause neuropathy. In analogy with pharmacological models of drug-receptor interactions, NTE inhibitors might have variable intrinsic activities to initiate neuropathy once attached to the protein. Strong neuropathic chemicals require about 70% inhibition of NTE, others 80-90%, and the least potent almost 100%. These differences have been amplified by means of promotion. Different levels of NTE inhibition as caused by different compounds were promoted by the same dose of phenylmethanesulfonyl fluoride to similar degrees of ataxia. Conversely nearly complete NTE inhibitions obtained in chicks with different chemicals were promoted to varying severities of ataxia. Protection from delayed polyneuropathy by the least neuropathic inhibitors can be explained by their weak intrinsic activity: occupying NTE, they prevent the binding of more neuropathic compounds. Methamidophos represents a particular example because it is protective at lower doses and neuropathic at high doses. Moreover, the levels of NTE inhibited by methamidophos which can be promoted to neuropathy are lower than those required for classic protective chemicals and higher than those of classic neuropathic OPs. This suggests that methamidophos has an intermediate position between the most and the least neuropathic NTE inhibitors.

Animals↗
PubMed1993

The search for the physiological functions of NTE; is NTE a receptor?

Neuropathy target esterase (NTE) was identified as the molecular target for organophosphate-induced delayed polyneuropathy several years ago but its physiological functions are still unknown. The mechanism which initiates neuropathy was thought to be a two step process: inhibition (phosphorylation) of NTE and aging of phosphorylated NTE. Depending on the occurrence of the second reaction (aging), inhibitors were ranked as neuropathic (forming an ageable NTE) and non-neuropathic (forming a non-ageable NTE). Non-neuropathic inhibitors protect from neuropathy if given before the neuropathic ones, because they occupy the catalytic centre of NTE. Thus the catalytic function of NTE seems irrelevant in maintaining the health of neurons. This paper reviews some new information concerning the interaction of NTE with its inhibitors as well as on a phenomenon called promotion of neuropathy. Some inhibitors which apparently form a non-ageable inhibited NTE were found to cause neuropathy, even though some of them must be given at very high doses. Moreover some 'non-neuropathic-protective' NTE inhibitors were found to exacerbate (promote) neuropathy when given after a neuropathic one. It is likely that the target for promotion is other than NTE. The hypothesis that NTE has some unknown receptorial functions where inhibitors act with different efficacy is discussed. NTE inhibitors have been ranked as full agonists (classic neuropathic inhibitors such as diisopropylfluorophosphate), partial agonists (protective or neuropathic, depending on the dose, such as methamidophos) and antagonists (protective, and neuropathic at the highest doses, such as phenylmethanesulfonyl fluoride). Age-related differences in the 'receptor' NTE might be responsible for the different sensitivities of juvenile and adult animals.

Animals↗
PubMed1993

Phenylmethanesulfonyl fluoride delays the recovery from crush of peripheral nerves in hens.

Several esterase inhibitors (carbamates, phosphinates and sulfonyl halides) have been shown to promote organophosphate-induced delayed polyneuropathy (OPIDP). The mechanism of promotion is not understood, but indirect evidence suggests impairments of peripheral nerve repair. Also, other toxic neuropathies, such as those caused by 2,5-hexanedione in hens and bromophenylacetylurea in rats, have been reported to be promoted by phenylmethanesulfonyl fluoride (PMSF). Hen sciatic nerve was crushed at the bifurcation. Either mild or heavy pressure was applied by forceps obtaining a mild and rapidly recovering lesion (possibly myelinic) or a more severe, long-lasting lesion (possibly axonal), respectively. Hens were then treated with PMSF (120 mg/kg s.c. or 200 mg/kg s.c. x 2, 24 h apart) either before (5-48 h) crush or afterwards (5-48 h). Controls received vehicle only. Animals were observed for reappearance of digit movements, and standing and walking ability. PMSF treatment did not change the clinical outcome when animals received a mild crush. In hens receiving the more severe crush the reappearance of digit movements and the complete clinical recovery were observed after 43 +/- 14 and 63 +/- 9 days, respectively. In animals treated with PMSF there was a significant delay in both reappearance of digit movements (56 +/- 11 days when PMSF was given 24 and 48 h before crush, and 55 +/- 10 days, when given 24 and 48 h after crush) and in clinical recovery (75 +/- 15 and 80 +/- 18 days, respectively). It is concluded that traumatic axonopathy as well as toxic neuropathies can be promoted by PMSF. Moreover, it appears that PMSF promotion involves a target and a mechanism which are present in healthy axons and do not need to be activated by the insult to the axon.

Animals↗
PubMed1992

Phenylmethanesulfonyl fluoride elicits and intensifies the clinical expression of neuropathic insults.

It has been recently reported that phenylmethanesulfonyl fluoride (PMSF) when given to hens after a neuropathic organophosphate (OP) promotes organophosphate-induced delayed polyneuropathy (OPIDP). Chicks are resistant to OPIDP despite high inhibition/aging of neuropathy target esterase (NTE), the putative target of OPIDP initiation. However, when PMSF (300 mg/kg s.c.) is given to chicks after di-butyl 2,2-dichlorovinyl phosphate (DBDCVP, 1 or 5 mg/kg s.c.), OPIDP is promoted. Inhibition/aging of at least 30% of NTE was thought to be an essential prerequisite for promotion to be elicited in adult hens. However, we observed in hens that when NTE is maximally affected (greater than 90%) by phenyl N-methyl N-benzyl carbamate (40 mg/kg i.v.), a non-ageable inhibitor of NTE, and then PMSF is given (120 mg/kg/day s.c. x 3 days) clinical signs of neuropathy become evident. Methamidophos (50 mg/kg p.o. to hens), which produces in vivo a reactivatable form of inhibited NTE, was shown either to protect from or promote OPIDP caused by DBDCVP (0.45 mg/kg s.c.), depending on the sequence of dosing. Because very high doses of methamidophos cause OPIDP, we considered this effect to be a "self-promoted" OPIDP. We concluded that NTE inhibitors might have different intrinsic activities for producing OPIDP once NTE is affected. Aging might differentiate highly neuropathic OPs, like DBDCVP, from less neuropathic OPs, like methamidophos, or from the least neuropathic carbamates, which require promotion in order for neuropathy to be expressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Clinical expression of organophosphate-induced delayed polyneuropathy in rats.

Single doses of certain organophosphates (OP), such as dibutyl-2,2-dichlorovinyl phosphate (DBDCVP) cause organophosphate-induced delayed polyneuropathy (OPIDP) in hens. Clinical effects correlate with inhibition of neuropathy target esterase (NTE) which is considered the target for this toxicity. Pre-treatment with non-neuropathic NTE inhibitors, such as phenylmethanesulfonyl fluoride (PMSF), protects from OPIDP. However, when given after OPs, these compounds promote OPIDP. Chicks are relatively resistant to OPIDP despite high NTE inhibition. It has also always been reported that rats represent a species which is resistant to OPIDP and that they might develop morphological but not clinical signs of OPIDP. We report here that clinical OPIDP can be produced in 3.5- and 6-month-old rats by DBDCVP (5 mg/kg s.c.) and that it correlates with high (> 90%) NTE inhibition. When PMSF (120 mg/kg s.c. x 2) was given after DBDCVP, OPIDP was promoted. Pretreatment with PMSF protected from OPIDP. We conclude that resistance to OPIDP in the rat is age-related, as it is in the hen.

Acetylcholinesterase↗