Organophosphate-induced Delayed Polyneuropathy Research Articles

An insight into neurotoxicity effects associated with Organophosphate exposure

Organophosphates comprise several groups of chemicals derived from phosphonic, phosphinic and phosphoric acids. The chemicals cause four major neurotoxic disorders: cholinergic syndrome, chronic organophosphate-induced neuropsychiatric disorder (COPIND), intermediate syndrome and organophosphate-induced delayed polyneuropathy (OPIDP). In the cholinergic syndrome, organophosphates exert their toxic effect through the inhibition of acetylcholinesterase. Patients with cholinergic syndrome experience several symptoms including sweating, lacrimation, salivation and rhinorrhea and respiratory difficulties. The primary symptoms in the intermediate syndrome are respiratory and proximal limb muscle weakness. In contrast, psychiatric conditions, such as depression and anxiety, have been reported in patients with COPIND. In OPIDP, patients experience acute cramping pain inside their calves and itchiness in the hands and feet, paresthesia and distal unresponsiveness.

An insight into neurotoxicity effects associated with Organophosphate exposure

Organophosphates comprise several groups of chemicals derived from phosphonic, phosphinic and phosphoric acids. The chemicals cause four major neurotoxic disorders: cholinergic syndrome, chronic organophosphate-induced neuropsychiatric disorder (COPIND), intermediate syndrome and organophosphate-induced delayed polyneuropathy (OPIDP). In the cholinergic syndrome, organophosphates exert their toxic effect through the inhibition of acetylcholinesterase. Patients with cholinergic syndrome experience several symptoms including sweating, lacrimation, salivation and rhinorrhea and respiratory difficulties. The primary symptoms in the intermediate syndrome are respiratory and proximal limb muscle weakness. In contrast, psychiatric conditions, such as depression and anxiety, have been reported in patients with COPIND. In OPIDP, patients experience acute cramping pain inside their calves and itchiness in the hands and feet, paresthesia and distal unresponsiveness.

Effectiveness of Ayurveda in Organophosphorus poisoning w.s.r. to Organophosphate-induced delayed polyneuropathy – A case Report.

Organophosphate (OP) compound poisoning is a major problem in a developing country like India mostly in rural areas. Organophosphorus pesticide inhibits acetylcholinesterase at nerve synapses. In the current case, 36-years patient was diagnosed with Organophosphate-induced delayed polyneuropathy (OPIDP) had a history of suicide attempts complaining of severe weakness, pain, and tingling sensation in Bilateral upper and lower limb after 15 days. Organophosphate-induced delayed polyneuropathy (OPIDP) develops after several weeks from exposure it is characterized by distal weakness and sensory loss which can be progressive. In Ayurveda the case was diagnosed and treated on the bases of Vishajanaya Vatavyadhi (Diseased induced by Poisoning) under the Umbrella of Urustambha. It was categorized in different stages of the disease and was treated accordingly with the help of different ayurvedic medications and Procedures for 9 follow-ups for 2 years.

Clinical profile of Intermediate Syndrome following Organophosphate Poisoning

Background: Organophosphate (OP) poisoning is a global issue, causing over 200,000 deaths annually especially in developing countries, such as Sri Lanka and India. Clinical presentation of a typical OP poisoning may follow three well-defined phases. The initial phase is an acute cholinergic crisis, after that Intermediate Syndrome (IMS) may develop within 24-96 hours, and lastly, Organophosphate-Induced Delayed Polyneuropathy (OPIDPN) may present after 2-3 weeks. The signs and symptoms of the IMS are weakness of the respiratory muscles, including the diaphragm, intercostal, accessory, neck, and proximal limbs muscles. The aim of this study was to highlight the clinical profile of the IMS following organophosphate poisoning. Methods: This descriptive, prospective, and cross-sectional study was conducted at the Teaching Hospital, Batticaloa, Sri Lanka, over a period of 6 months from March 1, 2017 to August 31, 2017. Results: Of the total 65 enrolled patients, 60% (n=39) were male. All patients ingested OP pesticide for deliberate self-harm and all of them had some degrees of initial cholinergic crises. The prevalence of IMS in the studied patients was 5.88%. All 5 patients with IMS had neck, facial and proximal limbs muscle weakness from whom, two cases (40%) had extra-ocular muscle paralysis. There was no in-hospital fatality among IMS patients. Conclusion: IMS is a rare and life-threatening problem in OP intoxication. Early diagnosis and intensive care management can prevent further complications and mortality. Prevalence of IMS in this study was lower than previous reports with almost similar clinical features.

Chlorpyrifos-Induced Delayed Neurotoxicity with A Rare Presentation of Flaccid Quadriplegia: A Diagnostic Challenge.

Chlorpyrifos is an organophosphate compound recognized as causing acute toxicity. However, organophosphate-induced delayed polyneuropathy (OPIDP), although rare, has also been described. We describe an unusual presentation of OPIDP with flaccid quadriplegia progressing to a locked-in-like syndrome, 30 days after a 60-year-old man voluntarily ingested chlorpyrifos. In the absence of specific treatment, the patient only recovered partial motor responses and the ability to communicate. The authors present this report in order to highlight a form of OPIDP which can hinder diagnosis due to its atypia and the delay in the onset of symptoms from initial contact with the toxicant.LEARNING POINTSOrganophosphate-induced delayed polyneuropathy (OPIDP) is a late presentation which is often overlooked despite causing significant morbidity.OPIDP can present in several forms, hindering the final diagnosis and consuming resources.

Organophosphate induced delayed pure motor neuropathy

Introduction Organophosphate poisoning (OP) is known to cause various neurological syndrome which include acute toxic effects due to cholinergic crisis and delay-ed syndrome characterised by motor-sensory polyneuropathy. Pure motor neuropathy with intact sensory conduction is rarely documented. We describe a patient who had a classic acute cholinergic crisis after exposure to organophosphate, with subsequent development of delayed pure motor axonal neuropathy. Case A 49 years old man was admitted to ICU with cholinergic crisis due to intentional ingestion of weedkiller (endosulphan and methamidophos). At the time of admission his GCS was 3, with pin point pupils, excessive salivation, hypotension and lacrimation. He was put on mechanical ventilator and treated with atropine. He recovered from acute cholinergic crisis but after two weeks, he developed weakness in legs and bilateral foot drop. Neurological examination showed wasting of the muscles of both legs with muscle power of grade 3/5 proximally and 0/5 distally. There was no weakness of the upper limbs. DTR were absent in the lower limbs. There was no sensory deficit. Nerve conduction studies (NCS) confirmed the diagnosis of severe axonal pure motor neuropathy with normal sensory response. He noticed improvement in strength in the legs over time but follow-up NCS after two years still shows axonal motor neuropathy. Conclusions Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1–4 weeks after single or short-term exposures. It is presumed to be due to phosphorylation and ageing of an enzyme in axons called neurotoxic esterase or neuropathic target esterase (NTE). Chronic neurotoxicity due to organophosphorus poisoning is dependent on several factors: chemical composition and dose of the organophosphates and the administration of anticholinergic for the cholinergic crisis.

Organophosphate Toxicity Presenting with Cholinergic Crisis, Intermediate Syndrome and Delayed Polyneuropathy in Succession: a Rare Presentation

Background : Organophosphate (OP) self poisoning is a major health hazard in a predominantly agrarian country like India. Acute cholinergic crisis and intermediate syndrome are well recognized manifestations of OP toxicity, delayed polyneuropathy being an unusual clinical event. Case Report: We describe a 30-year-old male with suicidal chlorpyrifos poisoning who presented with cholinergic crisis; developed intermediate syndrome subsequently and ultimately three weeks later landed up with OP induced delayed polyneuropathy (OPIDPN). Conclusion: This reported case emphasizes on the importance of strict vigilance and follow up in patients with OP toxicity in order to recognise and appropriately treat chronic toxicities like OPIDPN.

Soluble phenyl valerate esterases of hen sciatic nerve and the potentiation of organophosphate induced delayed polyneuropathy

Contrary to some organophosphorus esters (OPs), certain esterase inhibitors including sulfonyl halides, carbamates and phosphinates do not cause axonal neuropathy, but they may exacerbate traumatic and some chemical insults to axons. This phenomenon is referred to as the promotion/potentiation of axonopathies. We report here promotion studies of the organophosphate induced delayed polyneuropathy (OPIDP). This neuropathy correlates with inhibition/aging of neuropathy target esterase, but this enzyme is not the target of promotion. Soluble phenyl valerate (PV) esterases in peak I ( V 0) of hen sciatic nerve were analysed. When these activities were inhibited in vitro by a mixture containing mipafox – an OP that causes OPIDP – paraoxon and p-toluene sulfonyl fluoride – two esterase inhibitors that do not cause either neuropathy or promotion–, then the remaining activity was sensitive to classical promoters such as phenylmethane sulfonyl fluoride (PMSF) and phenylmethyl benzyl carbamate. This PV-activity was not inhibited in sciatic nerves of hens treated with di-isopropyl phosphorofluoridate, at a dose that causes OPIDP. When these birds were further dosed with PMSF a dose–response relationship was observed between inhibition of PV-esterases, as above defined, and the severity of clinical responses. These data suggest that the target of promotion is embraced in peak I ( V 0) of soluble proteins of hen sciatic nerve.

Peripheral nerve esterases and the promotion of organophosphate-induced neuropathy in hens

Several esterase inhibitors, not capable of causing peripheral neuropathy by themselves, exacerbate organophosphate-induced delayed polyneuropathy (OPIDP) and other axonopathies. This effect was called promotion of axonopathies and it was found not to be associated with inhibition of neuropathy target esterase (NTE), the molecular target of OPIDP. The search for an esterase as the target of promotion has started long ago, when an eterogeneous group of esterases-hydrolysing phenyl valerate (PV) was identified in hen's sciatic nerve by means of selective inhibitors. Correlation studies in vivo indicated that the target of promotion may have been among the proteins present in the soluble fraction. When this soluble PV-esterase activity was separated on a Sephacryl-S-300 column, correlation was found between promotion and its inhibition in vivo. The electrophoretic analysis of this fraction indicated the presence of several proteins. Subsequent ion-exchange chromatography identified a protein of about 80 kDa molecular weight that was associated with PV-esterase activity. The inhibition of this activity did also correlate with promotion. The sequence of this protein identified it as ovotransferrin, but commercial preparations of ovotransferrin were found to lack PV-esterase activity. Binding experiments on this purified PV-activity and on commercial ovotransferrin using radiolabelled promoters were inconclusive. Titration of this PV-activity showed that about 20–30% of it is resistant to high concentrations of several inhibitors, suggesting heterogeneity of the fraction. In fact, bi-dimensional electrophoresis indicated the presence of several proteins. Finally, in vivo correlation experiments with p-toluensulfonyl fluoride showed that whereas this chemical does not promote OPIDP induced by dibutyl dichlorovinyl phosphate, it does inhibit about 80% of this PV-activity. In conclusion, available data indicate that the target of promotion is unlikely to be ovotransferrin. However, all promoters identified so far are esterase inhibitors suggesting that the target of promotion might be, indeed, a protein with esteratic activity.

Follow-up study on psychic and neuropathic delayed effects of acute organophosphorus pesticides poisoning

To study the delayed effect on neuropsychopathy and its related factors after acute organophosphorus pesticides poisoning (AOPP). Two hundred and fifty-seven cases of AOPP in the observation period were chosen to follow-up 2 months later from the 4 county hospitals in Shandong Province where the incidence of organophosphorus pesticide poisoning is high. Nine cases of organophosphate induced delayed polyneuropathy (OPIDP) were found and the incidence rate was 3.5%. The occurrence of OPIDP were related to the need for emergent artificial respiration, and the degree of poisoning, and the kinds of organophosphorus pesticides (Ops). The positive rate of symptoms of peripheral nerves, central nerves and psychogeny except auditory and visual hallucination after poisoning was significantly higher than that before (P < 0.05). The patient's situation of health, economy and work became statistically worse (P < 0.05). We found some had delayed effects on neuropsychopathy after AOPP which could debase the patient's life quality. The control measure should be administered as early as possible.

Organophosphate-Induced Delayed Polyneuropathy

Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures. Cramping muscle pain in the lower limbs, distal numbness and paraesthesiae occur, followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include high-stepping gait associated with bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In time, there might be significant recovery of the peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be a permanent outcome of severe OPIDP. Human and experimental data indicate that recovery is usually complete in the young. At onset, the electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve with electromyographical signs of denervation. Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination. Neuropathy target esterase (NTE) is thought to be the target of OPIDP initiation. The ratio of inhibitory powers for acetylcholinesterase and NTE represents the crucial guideline for the aetiological attribution of OP-induced peripheral neuropathy. In fact, pre-marketing toxicity testing in animals selects OP insecticides with cholinergic toxicity potential much higher than that to result in OPIDP. Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity. However, this was not the case with certain triaryl phosphates that were not used as insecticides but as hydraulic fluids, lubricants and plasticisers and do not result in cholinergic toxicity. Several thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate have been reported, whereas the number of cases of OPIDP as a result of OP insecticide poisoning is much lower. In this article, we mainly discuss OP pesticide poisoning, particularly when caused by chlorpyrifos, dichlorvos, isofenphos, methamidophos, mipafox, trichlorfon, trichlornat, phosphamidon/mevinphos and by certain carbamates. We also discuss case reports where neuropathies were not convincingly attributed to fenthion, malathion, omethoate/dimethoate, parathion and merphos. Finally, several observational studies on long-term, low-level exposures to OPs that sometimes reported mild, inconsistent and unexplained changes of unclear significance in peripheral nerves are briefly discussed.

Toxicological assessment of isomeric pesticides: a strategy for testing of chiral organophosphorus (OP) compounds for delayed polyneuropathy in a regulatory setting

Many compounds, including some pesticides, contain structural centres of asymmetry, which convey the property of a type of stereoisomerism known as chirality. Such compounds can exist in two or more forms, depending on the number of chiral atoms and are termed stereoisomers or enantiomers. Stereoisomers of a particular compound can have different biological properties; one such of particular importance for toxicological evaluation, is the potential for differences in metabolic disposal of and binding of stereoisomers to molecular targets in the cell. The combination of differential metabolism of chiral organophosphorus (OP) pesticides and opposing stereoselectivity of inhibition of neuropathy target esterase (NTE) and acetylcholinesterase (AChE) can affect the value of the hen test, performed to OECD guidelines, in predicting the potential to cause organophosphate-induced delayed polyneuropathy (OPIDP) in humans. This is a mixed central and sensory and motor neuropathy. The experimental data on structural analogues of the pesticide methamidophos and the evidence for stereoselective OPIDP are reviewed and a model is given demonstrating how the properties of a chiral OP can result in the neuropathic potential not being detected by the standard hen test. A strategy for the assessment of a racemic mixture comprised of two OP enantiomers for the potential to induce OPIDP is outlined. The strategy uses information from structure activity relationships (SAR), in vitro tests and in vivo tests to allow risk assessment decisions to be made. It is suggested that the potential for stereoselective toxicity of pesticides should be routinely considered in regulatory assessments.

Organophosphate induced delayed polyneuropathy.

This review discusses the current understanding of organophosphate induced delayed polyneuropathy (OPIDP) with emphasis on molecular mechanisms, pathogenesis and possibilities for prevention/therapy. OPIDP is a rare toxicity caused by certain organophosphorus compounds (OP) characterized by degeneration of some long axons in the central and peripheral nervous system that appear about 2-3 weeks after exposure. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). NTE can be inhibited by two types of inhibitors: a) phosphates, phosphonates, and phosphoramidates, which cause OPIDP when >70% of the enzyme is inhibited, and b) phosphinates, carbamates, and sulfonyl halides which inhibit NTE and cause either protection from, or promotion, of OPIDP when given before or after a neuropathic OP, respectively. The ability of a NTE inhibitor to cause OPIDP, besides its affinity for the enzyme, is related to its chemical structure and the residue left attached to the NTE. If such residues undergo the aging reaction i.e. the loss of an alkyl group bound to the enzyme, those OPs usually have a high likelihood of causing OPIDP. Protection from neuropathic doses of OP inhibitors is obtained when NTE is inhibited with nonageable inhibitors. Promotion of OPIDP involves another site besides NTE because it can occur when all NTE is affected. It is now known that this other site is similar to NTE in that it is also sensitive to mipafox but at much higher concentrations. Promotion affects either the progression or expression of OPIDP after the initial biochemical effect on NTE. Some recent observations suggest that development of OPIDP in hens can be influenced by atropine, oximes and methylprednisolone when they are given before or soon after neuropathic OPs.

Promotion of organophosphate induced delayed polyneuropathy by certain esterase inhibitors

Organophosphate induced delayed polyneuropathy (OPIDP) is an axonopathy caused by single doses of some organophosphates (OPs). Other OPs, sulphonyl halides, carbamates, thiocarbamates and phosphinates do not cause axonopathy but elicit or intensify the clinical expression of OPIDP when given after a neuropathic OP (promotion of OPIDP). One enzymatic activity (M200) was identified by means of selective inhibitors in hen peripheral nerve crude homogenates. Promotion of OPIDP initiated with several OPs was found to correlate with inhibition of M200 when various promoters were given to hens. Most M200 is in the soluble fraction of peripheral nerves and was separated from other esterases by means of molecular exclusion chromatography. In a second series of experiments, inhibition of this fraction also correlated with promotion when induced by the same chemicals. Further ion exchange chromatography identified a protein (60 kDa MW): the inhibition of its enzymatic activity correlated with promotion in another series of in vivo experiments. Biochemical and structural analyses of this protein are underway. Several experiments indirectly suggest that promotion may be related to mechanisms of repair and/or compensation of peripheral nerves. These include the observation that promotion results in clinical expression of biochemical lesions that otherwise would be well compensated, that promotion is not specific because axonopathies of other etiology are also exaggerated, and that promoters are effective when given several days before the neuropathic insult. Moreover, developing animals are more resistant to promotion.

Onset of grip- and pinch-strength impairment after acute poisonings with organophosphate insecticides.

The course of organophosphate-induced delayed polyneuropathy (OPIDP) in humans has not been quantitatively measured in epidemiologic studies. This study evaluated the association of acute OP poisonings with motor neurologic impairment. Hand grip and pinch strength were evaluated among 62 Nicaraguan men hospitalized for acute OP poisoning between 1992 and 1996; 39 cattle ranchers and fishermen who had never experienced pesticide poisoning were controls. Exposure categories were moderate and severe poisonings with neuropathic and non-neuropathic OPs. Strength was measured at hospital discharge and seven weeks after poisoning. Grip and pinch strength were impaired among all OP-poisoned subjects at both examinations, more noticeably among those poisoned with OPs with suspected neuropathic effects, methamidophos and chlorpyrifos. In those with severe poisonings with neuropathic OPs, impairments were more marked among intentional than among occupational poisonings. The performances of suicidal subjects worsened at the second examination, consistent with OPIDP. Early motor impairment at the time of hospital discharge is consistent with cholinergic depolarization blockade after acute poisoning. The persistence of deficits in motor strength in all severely poisoned patients regardless of pesticide type was unexpected, and may reflect persistent cholinergic blockade or intermediate syndrome, neuropathy, or a combination of these.

Effects of S-ethyl hexahydro-1H-azepine-1-carbothioate (molinate) on di-n-butyl dichlorovinyl phosphate (DBDCVP) neuropathy.

Certain esterase inhibitors protect from organophosphate-induced delayed polyneuropathy (OPIDP) when given before a neuropathic organophosphate by inhibiting neuropathy target esterase (NTE). In contrast, they can exaggerate OPIDP when given afterwards and this effect (promotion) is associated with inhibition of another esterase (M200). In vitro sensitivities of hen, rat, and human NTE and M200 to the active metabolites of molinate, sulfone, and sulfoxide, were similar. NTE and M200 were irreversibly inhibited (> 78%) in brain and peripheral nerve of hens and rats given molinate (100-180 mg/kg, sc). No clinical or morphological signs of neuropathy developed in these animals. Hens and rats were protected from di-n-butyl dichlorovinyl phosphate neuropathy (DBDCVP, 1 and 5 mg/kg, sc, respectively) by molinate (180 or 100 mg/kg, sc, 24 h earlier, respectively) whereas 45 mg/kg, sc molinate causing about 34% NTE inhibition offered partial protection to hens. Hens treated with DBDCVP (0.4 mg/kg, sc) developed a mild OPIDP; molinate (180 mg/kg, 24 h later) increased the severity of clinical effects and of histopathology in spinal cord and in peripheral nerves. Lower doses of molinate (45 mg/kg, sc), causing about 47% M200 inhibition, did not promote OPIDP whereas the effect of 90 mg/kg, sc (corresponding to about 50-60% inhibition) was mild and not statistically significant. OPIDP induced by DBDCVP (5 mg/kg, sc) in rats was promoted by molinate (100 mg/kg, sc). In conclusion, protection from DBDCVP neuropathy by molinate is correlated with inhibition of NTE whereas promotion of DBDCVP neuropathy is associated with > 50% M200 inhibition.

Effects of atropine, trimedoxime and methylprednisolone on the development of organophosphate-induced delayed polyneuropathy in the hen

In this study we have examined the effects of atropine, trimedoxime (TMB-4) and methylprednisolone (MP) on the development of organophosphate-induced delayed polyneuropathy (OPIDP) in the hen. The birds were treated with standard neuropathic dose of diisopropylfluorophosphate (DFP) (1.1 mg/kg, sc), which produced OPIDP that could be graded as 5 on the 8-point scale, and the development of OPIDP was observed for the next 22 days. The results obtained have shown that atropine (20 mg/kg, ip), TMB-4 (15 mg/kg, im) and MP (2 or 10 mg/kg, ip) either alone or in different combinations are able to improve the condition of the birds. The most potent effect was obtained with atropine, TMB-4 (given 20 min before DFP) and MP (2 mg/kg, sc, given 20 min before and at 48 hour intrevals after poisoning) since the signs of OPIDP could hardly be seen (grade 1 at the 8-point scale). When TMB-4 and MP were given 15 or 40 min after DFP the protective/therapeutic effects of these drugs appeared to be diminished since walking disorders were more serious and graded as 2 or 4, respectively. The possible mechanisms of the action of the drugs in respect to OPIDP are discussed. In conclusion, the results of this study have shown that it is possible to prevent the development of DFP-induced OPIDP in the hen by treatment with atropine, trimedoxime and methylprednisolone when they were given before or soon after DFP.

Promoters and promotion of axonopathies

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 μM) and sensitive to mipafox (50 μM). 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.

Testing for Organophosphate‐Induced Delayed Polyneuropathy

Organophosphorous compounds may cause two distinct types of toxicity: acute cholinergic toxicity and organophosphate-induced delayed polyneuropathy (OPIDP). The ability of a compound to cause OPIDP is assessed as described by administering the compound to hens and screening the brain, spinal cord, and peripheral nerves for neuropathy target esterase activity to detect OPIDP and acetylcholinesterase activity to rule out the acute toxicity. This assay can also be used as part of a screen for protective agents.

Promotion of organophosphate induced delayed polyneuropathy by certain esterase inhibitors

Certain esterase inhibitors elicit or intensify the clinical expression of various insults to axons. This phenomenon was called promotion of axonopathies because these chemicals are not additive neurotoxicants nor do they interfere with the pharmacokinetics. Characterization of promotion was carried out by using organophosphate induced delayed polyneuropathy (OPIDP) as a model. The search for a physiological explanation of promotion has the following background: (1) Promotion expresses clinically the biochemical lesions which are otherwise well compensated (such as 30/40% neuropathy target esterase (NTE) inhibition by neuropathic organophosphates). (2) Promotion is not specific because axonopathies of different origin are affected. (3) Promoters are effective when given several days before the neuropathic insult. (4) Promotion is less effective in young animals as compared with adults. (5) Promotion occurs when axons, but not necessarily the cell body, are targeted by promoters. (6) Repeated dosing with a promoter failed to produce axonopathy. Based on this evidence it is suggested that promotion might interfere with a mechanism(s) of compensation and/or repair of long axons. The target of promotion of axonopathies is thought to be similar or linked to NTE which is defined as the phenyl valerate esterase activity (PVE) in nervous tissues resistant to paraoxon and sensitive to mipafox (40 and 50 μM, pH 8.0, 20 min, respectively). Mipafox (50 μM) resistant PVEs include some activity sensitive to the promoter phenylmethane sulfonylfluoride (PMSF) but no correlation was found between its inhibition and promotion. A complete titration curve of paraoxon-resistant PVEs by mipafox (0–1 mM) dissected, besides NTE (I50 about 10 μM), another PVE with an I50 of approximately 200 μM. This enzyme was present in hen brain, spinal cord and peripheral nerve, corresponding to about 10, 20 and 30% of NTE activity, respectively, and was sensitive both in vitro and in vivo to promoters and much less so to neuropathic NTE inhibitors. By means of chromatography, other workers have identified in soluble extracts of peripheral nerves two forms of mipafox-sensitive PVEs with different molecular weights and different sensitivity to mipafox. These might correspond to NTE and to the other enzyme. Inhibition in vivo of the latter also correlated with promotion.