Peripheral Nervous System Effects and Delayed Neuropathy

CHAPTER

~ 5

Peripheral Nervous System Effects and Delayed Neuropathy ANGELO MORETTO AND MARCELLO LOTYI Universitgt degli Studi di Padova, Padova, Italy

I. I N T R O D U C T I O N

days). In addition, the cleavage of one of the bound alkyl groups of the phosphoryl residue, known as aging, may subsequenfly occur. This leaves a negative charge at the residue attached to the active site. In this way, the enzyme becomes permanently inhibited (Aldridge and Reiner, 1972). The putative target of OPIDP is a neural protein with esteratic activity called neuropathy target esterase (NTE). It is thought that the mechanism of axonal degeneration is initiated by phosphorylation and subsequent aging of at least 70% of NTE (Johnson, 1990). Among OPs, with general structure R1R2P(O or S)X, that are capable of causing OPIDP, several factors determine their potential to inhibit NTE. For instance, phosphonates and phosphoroamidates are more potent than their homologous phosphates; increasing the carbon chain length of R1 and R2 also increases the inhibitory power. Characteristics that decrease this potency are bulky hydrophilic or nitrophenol groups at X and thioether linkages at X (Johnson, 1982). NTE inhibition/aging occurs within hours after dosing and NTE activity returns to normal well before the onset of clinical and morphological signs (Caroldi and Lotti, 1982). It has been shown that the 70% threshold inhibition is also required after repeated exposures. In fact, even cumulative doses higher than a single effective one failed to cause OPIDP when threshold of inhibition was not reached. Only when the doses and the dosing interval did not allow substantial resynthesis of the enzyme could the threshold be reached and OPIDP initiated (Lotti and Johnson, 1980). Studies on the sensitivity of the target enzymes of a variety of OPs showed that the comparative inhibitory power of OPs against hen acetylcholinesterase (ACHE) and NTE in vitro correlates with their comparative effects in vivo (i.e., death or delayed neuropathy). This correlation can be numerically expressed by the ratios ACHE ICs0/NTE IC50 in vitro and LD50/neuropathic dose in vivo. Moreover, comparison of the in vitro effects seen with hen and human enzymes indicated that the hen animal model well predicts the development of OPIDP in humans (Lotti and Johnson, 1978). Therefore,

The relevant effect of organophosphates (OPs) on the peripheral nervous system (PNS) is the organophosphate-induced delayed polyneuropathy (OPIDP). OPIDP is characterized by distal degeneration of long and large-diameter motor and sensory axons of both peripheral nerves and spinal cord. Several species, including man, are sensitive to OPIDP, and the animal model is the hen (Johnson, 1975a). OPIDP is caused by a single dose of some, but not all, OPs, and several reviews have summarized available experimental data on individual compounds (Johnson, 1975b, 1982; Lotti, 1992). Other OPs have been tested for their delayed neurotoxic potential by Tkachenko et al. (1992), Jokanovid (1993), Jokanovid et al. (1995), Abdelsalam (1999), Carrington (1989), Mortensen and Ladefoged (1992), Daugherty et al. (1996), and Moretto et al. (1994). Rodents are relatively resistant to OPIDP. In particular, clinical and morphological signs of OPIDP can be elicited in the rat by very high single or repeated doses of neuropathic OPs (Veronesi, 1984; Padilla and Veronesi, 1985; Moretto et aL, 1992a). Neuropathology not accompanied by clinical signs was observed in mice. The distribution of the lesions was slightly different from that observed in the rat (Veronesi et al., 1991). The clinical and morphological onset of OPIDP in hens generally occurs between 10 and 15 days after dosing, but depending on the dose, it can be as short as 6 or 7 days after poisoning. Full expression of clinical signs usually occurs within 3-5 days. In humans, the onset and the progression of the disease are generally somewhat slower.

II. M E C H A N I S M OF O P I D P OPs and carbamates (CMs) react covalenfly as pseudosubstrates at the catalytic center of a variety of serine hydrolases. Contrary to true substrates, the rate of hydrolysis of the carbamylated enzymes is slow (minutes to hours) and that of phosphorylated enzymes is extremely slow (hours to Toxicology of Organophosphate and Carbamate Compounds

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ratios of inhibitory powers for AChE and NTE and/or that of lethal dose/neuropathic dose represent the key dose-effect relationships of each OR Consequently, they are among the fundamental criteria for the etiological attribution of cases of peripheral neuropathy in humans when sorting out various other differential diagnoses and etiologies. Although OPIDP hazard is shared by several OPs, the risk of developing OPIDP is actually rather small for existing commercial insecticides. In fact, premarketing toxicity testing in animals selects OPs with a cholinergic toxicity potential much higher than that which causes OPIDP (e.g., the ratios are <0.1 for the compounds in current use) (Moretto, 1999; Organisation for Economic Co-operation and Development, 1995): Consequently, neuropathic doses of these OPs will cause a severe cholinergic syndrome before the onset of clinical and morphological OPIDE Thus, OPIDP may develop in humans after very large exposures only (e.g., suicide attempts), causing unambiguous cholinergic toxicity. However, this is not the case for certain triaryl phosphates that do not cause cholinergic toxicity and have been used as hydraulic fluids, lubricants, or plasticizers (World Health Organization, 1990). Currently used triarylphosphates do not contain the neuropathic isomer tri-o-cresyl phosphate (Mackerer et al., 1999). OPs, as well as other non-OP inhibitors such as CMs and sulfonyl fluorides, also covalently react with NTE but cannot undergo the aging reaction. As a consequence, these inhibitors do not cause OPIDE and when given to experimental animals before a neuropathic OP, they protect from OPIDP when they occupy at least 30% of NTE active sites. Thus, the loss of NTE catalytic activity is not the mechanism leading to axonal degeneration (Johnson, 1990; Lotti et al., 1993). Hypotheses that have been proposed to explain the consequences of these OP-NTE interactions include either a loss of a nonesterase function of NTE that is essential for the axon or a gain of a toxic function of phosphorylated/aged NTE (Glynn, 1999). It has been shown that the relationship between the degree of NTE inhibition and the severity of OPIDP changes according to the compound involved. Whereas certain compounds cause OPIDP with a minimum of 70% NTE, others require a higher, almost complete, inhibition to cause OPIDE For this reason, it was proposed that all NTE inhibitors may have the potential to cause neuropathy, in analogy with pharmacological models of drug-receptor interactions (Lotti et al., 1993). According to this hypothesis, NTE inhibitors may have variable intrinsic activities to trigger the mechanism leading to axonal degeneration. Classic neuropathic OPs, such as diisopropyl fluorophosphate (DFP), are considered strong agonists since they cause OPIDP with 70% NTE inhibition, whereas nonageable inhibitors, such as CMs and sulfonyl fluorides, are considered partial agonists and therefore are among the weakest at initiating OPIDE requiting almost 100% NTE inhibition. Their weak agonist activity is also consistent with their protective effect when causing lower NTE inhibition.

Young animals are relatively resistant to OPIDE Although the pool of PV-esterases and NTE-specific activity show some age-related changes, OPs affect NTE in chicks as in hens (Moretto et al., 1991). The threshold level of inhibition required to trigger the initiation mechanism was found to be much higher (>90%) in young animals than in adults (Peraica et al., 1993). In addition, in young chicks (20 days old) OPIDP is mild and clinical signs show predominant spasticity rather than flaccidity, suggesting selective toxicity to the spinal cord. This was confirmed by histopathological lesions observed in spinal cord, but not in peripheral nerves, in 2-week-old chicks and by the earlier appearance of spinal cord lesions in 10-week-old chicks (Funk et al., 1994). Young animals recover from OPIDE The extent and timing of recovery depend on age and severity of the lesions, being shorter in younger and less severely affected animals. To explain the resistance of young animals, the hypothesis was made that they can compensate for a higher level of disruption because of their efficient repair systems (Lotti, 2002a). The events leading to axonal degeneration following NTE inhibition/aging are unknown, except for a deficit of retrograde axonal transport (Moretto et al., 1987). It was shown in hens that retrograde axonal transport is selectively impaired within a few days after poisoning, and the deficit progresses and reaches its maximum before the onset of OPIDE However, the cascade of events from NTE inhibition/aging to impairment of retrograde axonal transport and axonal degeneration is not understood.

III. STUDIES OF THE NTE PROTEIN NTE is present not only in neurons but also in a variety of nonneuronal tissues (Moretto and Lotti, 1988; Williams, 1983) but not in glial cells (Glynn et al., 1998). NTE from various species, including man, is a homolog of a protein required for brain development in Drosophila (Kretzschmar et al., 1997) and contains a domain that is highly conserved from bacteria to man (Lush et al., 1998). Studies conducted on the recombinant domain of NTE purified from bacterial lysates or by using differential inhibition with mouse brain NTE both in vitro and in vivo suggested that membrane lipids are putative cellular substrates of this enzyme (Van Tienhoven et al., 2002; Quistad et al., 2003; Quistad and Casida, 2004). In mammalian cell cultures, it was found that NTE is one of the enzymes that catalyze the deacylation of phosphatidylcholine to glycerophosphocholine. However, the relative contribution of NTE and calciumindependent phospholipase A2 plus lypophospholipases to this reaction has not been established (Zaccheo et al., 2004). This resulted in the hypothesis that NTE may be involved in intraneuronal membrane trafficking and lipid homeostasis. However, since this activity of NTE is inhibited in vitro by the nonneuropathic compound phenylpentyl

CHAPTER 25 9 Delayed Neuropathy phosphinate (Zaccheo et al., 2004), it is obviously not essential for the maintenance of the axon and therefore not correlated with the initiation of axonal degeneration. The catalytic domain of NTE (NEST) associated with phosphatidyl choline liposomes facilitates transmembrane ionic conductance (Forshaw et al., 2001). The facilitation is partially inhibited by neuropathic OPs, such as DFP and phenyl saligenin phosphate, but not by nonneuropathic covalent NTE inhibitors, such as phenylpentyl phosphinate and phenylmethane sulfonyl fluoride (PMSF). Whether this effect has any relevance to the mechanism of OPIDP is unknown. NTE has an essential role in fetal development. Winrow et al. (2003) and Moser et al. (2004) showed that knockout Nte - / - mice died in utero probably as a result of failed placental development, whereas Nte +/- animals were viable and fertile. NTE mutation did not affect preimplantational growth; additionally, impairment of vasculogenesis in the yolk sacs and embryos of null mutant conceptuses suggested that NTE is also required for normal blood vessel development (Moser et al., 2004). Conditional inactivation of the NTE gene in the mouse peripheral and central nervous systems resulted in elimination of NTE protein in the nervous system from embryonic day 11. Although this was compatible with embryonic nervous system development, these animals displayed neuronal degeneration and loss of endoplasmic reticulum in the hippocampus, thalamus, and cerebellum at 6 but not 2 weeks of age (Akassoglou et al., 2004). In summary, although there is compelling evidence of the involvement of NTE in OPIDP initiation, its role in axonal degeneration remains obscure.

IV. OTHER MECHANISTIC STUDIES Several studies have investigated the hypothesis that the development of OPIDP may involve protein kinase-mediated phosphorylation of cytoskeletal proteins. Most of this body of research on the phosphorylation of endogenous proteins was summarized by Abou-Donia (2003). However, it has provided equivocal results and, as a whole, little understanding of the molecular mechanism(s) of OPIDP considering, for instance, that results on endogenous phosphorylation of proteins were different according to the compound, neuropathic doses, and time of assay (Seifert and Casida, 1982; Patton et al., 1983, 1985, 1986; Hugghins and Richardson, 1999; Gupta and Abou-Donia, 1995; Gupta et al., 2000). Distinction should be made among the effects observed at different times during the development of OPIDP. Thus, early events include the altered expression of neurofilament subunits, which has been detected in hen spinal cord of animals treated with neuropathic doses of DFP as early as 1 day after dosing (Gupta et al., 2000). Middle-molecular-weight neurofilament protein expression was increased, whereas that of high- and low-molecular-weight neurofilament proteins

363

was decreased. Also, accumulation of these proteins was observed in the cytoskeletal inclusions in DFP-treated hen spinal cord. Although these changes were not present in the brain, a part of the central nervous system not affected by OPIDP, the pathophysiological significance of these changes remains unclear. Intermediate events include erratic changes of protein kinases A and C (Gupta and Abou-Donia, 2001), glyceraldehyde-3-phosphate dehydrogenase (Damodaran et al., 2002a), phosphorylated cAMP-response element binding protein (Damodaran et al., 2002b), and c~-tubulin expressions (Damodoran et al., 2001), which have all been detected during OPIDP development in the spinal cord of DFP-treated animals. Late changes include the increased Ca 2+ calmodulindependent autophosphorylation of hen brain and spinal cord proteins from animals paralyzed by TOCP treatment (Patton et al., 1986; Suwita et al., 1986). Several cytoskeletal proteins also seem to be affected. For instance, Ca 2+ calmodulin-dependent phosphorylation of several amino acids in tau proteins was enhanced by brain supernatants of DFP-treated animals. This effect may be associated with a small increase in Ca 2+ calmodulin-dependent protein kinase IIoL subunit mRNA expression that was observed 5-10 days after similar treatment (Gupta et al., 1998), followed by an equally small increase in the protein level (Gupta and Abou-Donia, 2001). The increase in phosphorylation of tau proteins may cause a decrease in tau microtubule binding, and it has been hypothesized that this would cause destabilization of microtubules and thus OPIDP (Gupta and Abou-Donia, 1998, 1999). Similarly, an increased phosphorylation of microtubule-associated protein-2 (Abou-Donia et al., 1993) and a small decrease in tubulin polymerization were observed in hen brain of DFP-paralyzed animals (Gupta and Abou-Donia, 1994). Moderate depletion of ATP was observed in peripheral nerves of hens with severe OPIDP (Massicotte et al., 2001). Most of these effects were measured 18-20 days after dosing, when animals were already paralyzed. Therefore, it is difficult to ascertain whether they were the cause or the consequence of axonal degeneration. Moreover, similar changes were observed in young rats (Choudhary et al., 2001), which are known to be resistant to OPIDP (Moretto et al., 1992a). Several studies investigated the possible role of calcium homeostasis disturbances in OPIDP pathogenesis, but results were inconsistent across various OPs and species (Suwita et al., 1986; E1-Fawal et al., 1989; Luttrell et al., 1993; Barber et al., 2001; Piao et al., 2003; Wu et al., 2003; Choudhary and Gill, 2001). Finally, several studies investigated various possible mechanisms in vitro (Pope et al., 1995; Sachana et al., 2001a,b; Fowler et al., 2001; Hong et al., 2003; Sales et al., 2004). However, results are very preliminary and do not add much to our understanding of OPIDP pathogenesis.

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SECTION IV. O r g a n

Toxicity

V. C L I N I C A L A S P E C T S O F O P I D P I N M A N Several thousand cases of OPIDP in humans caused by accidental ingestion of TOCP have been reported and reviewed by Inoue e t al. (1988). TOCP and related triaryl phosphates do not cause cholinergic toxicity and have been used as plasticizers, lubricants, and hydraulic fluids. Triaryl phosphates used as jet-engine lubricants contain very little, if any, TOCP (Mackerer e t al., 1999). In contrast with triaryl phosphates, many fewer cases of OPIDP have been convincingly attributed to OP insecticides, as summarized in Table 1. Clinical, electrophysiological, and histopathological details of these cases, and criteria for their inclusion in Table 1, have been discussed elsewhere (Lotti and Moretto, 2005). In addition to those reported in Table 1, cases of peripheral neuropathy likely caused by the CMs carbaryl, carbofuran, and metolcarb have been reported (Dickoff et al., 1987; Umehara e t al., 1991; Yang e t al., 2000). In these cases, the dose was very high, as judged by the severe cholinergic syndrome. Perhaps, the very effective antidotal and supportive treatment for cholinergic toxicity allowed a very high NTE inhibition in v i v o , similar to that associated with neuropathy in animals given repeated doses of CMs. In these animals, repeated dosing allowed some spontaneous reactivation of AChE between doses and, con-

TABLE 1.

sequently, the survival of the animals to doses causing almost complete NTE inhibition (Lotti e t al., 1993). Symptoms of OPIDP usually appear 2 or 3 weeks after a single dose; this delay depends on both the kinetic characteristics of the compound and the dose. After a high dose, it can be as short as 10 days, whereas the onset after poisoning by an OP with prolonged kinetics or at a relatively low dose may be up to 5 weeks. In the case of poisoning by insecticides, both cholinergic and intermediate syndromes have subsided before the onset of OPIDP (Lotti et al., 1984). Within a few days of the onset of symptoms, the full clinical expression of OPIDP is usually observed, and in the absence of further exposure, no progression of the disease occurs. The onset of symptoms and signs and their full development are more variable and less definable following repeated exposures to non-AChE triaryl phosphates. In fact, these compounds do not have AChE activity, and exposure may occur over several days without symptoms and the threshold of NTE inhibition may be reached as a consequence of a cumulative effect that overcomes the capability of the neurons to resynthesize NTE. The usual initial complaint is cramping musclepain in the lower limbs, followed by distal numbness and paresthesia. Progressive weakness then occurs, together with depression of patellar and Achilles reflexes. When severe,

Compounds Reported to Cause OPIDP in Humans a

Compound

Case reports in humans

Chlorpyrifos Dichlorvos

Lotti et al. (1986), Tracy and Gallagher (1990) Vasilescu and Florescu (1980), Wadia et al. (1985), Vasconcellos et al. (2002), Sevim et al. (2003) Moretto and Lotti (1998) Senanayake and Johnson (1982), McConnell et al. (1999), Eray et al. (1995), Moretto and Lotti (1998), Aygun et al. (2003) Bidstrup et al. (1953) Hierons and Johnson (1978), Vasilescu and Floreseu (1980), Johnson (1981) Vasilescu et al. (1984), Shiraishi et al. (1983), Niedzella et al. (1985), Csik et al. (1986) Jedrzejowska et al. (1980), De Kort et al. (1986) Inoue (1988) (review), Senanayake (1981) (in youngs), Goldenstein et al. (1988) (in youngs)

Isofenphos Methamidophos

Mipafox Trichlorfon

Trichlornat Triaryl phosphates

Phosphamidon/mevinphos

Chuang et al. (2002)

Reference for OPIDP in hens

Richardson (1995) Caroldi and Lotti (1981) Francis et al. (1985) Johnson (1981)

Barnes and Denz ( 1953) Johnson (1981)

Johnson (1975a,b) World Health Organization (1990) (review), Weiner and Jortner (1999) (review) Jokanovid et al. (1995)

aln addition, several unconvincing cases attributed to these compounds have been reported, such as those associated with chlorpyrifos (De Silva et al., 1994; Aiuto et al., 1993; Chattarjee and Sarma, 2003; Kaplan et al., 1993; Meggs, 2003), isofenphos (Catz et al., 1988), and methamidophos (Sun et al., 1998; De Haro et al., 1999). Several other OP insecticides have been reported to cause OPIDP. However, these reports are not convincing for several reasons, including lack of details and information, no evidence of OPIDP in experimental animals, and more likely alternative etiologies. Compounds involved in these case reports were fenthion (Aygun et al., 2003; Martinez-Chuecos et al., 1992), malathion (Monje Argiles et al., 1990; Dive et al., 1994; Rivett and Potgieter, 1987), mecarbam (Stamboulis et al., 1991), omethoate (Curtes et al., 1981), dimethoate (Sol~ Violhn et al., 1985; Sahin et al., 1994), parathion (De Jager et al., 1981; Alonso et al., 1983; Nisse et al., 1998;Aygun et al., 2003; Carod-Artal and Speck-Martins, 1999), and merphos (Fisher, 1977).

CHAPTER 25 9 Delayed Neuropathy symptoms and signs of neuropathy appear in the arms and forearms. Physical examination reveals wasting and flaccid weakness of distal limb muscles, especially in the legs. Objective evidence of sensory loss is usually less severe or even absent (Moretto and Lotti, 1998). Signs include a characteristic high-stepping gait associated With bilateral footdrop. Quadriplegia with foot- and wristdrop as well as pyramidal signs are observed in the most severe cases. A detailed clinical description of a case series of TOCP poisoning can be found in Susser and Stein (1957). Functional recovery occurs with time in less severe cases, with most distal involvement and sparing of spinal cord axons. Otherwise, pyramidal and other signs of central neurological involvement may become more evident, and spastic ataxia may be a permanent outcome of severe OPIDP (Morgan and Petrovich, 1978; Susser and Stein, 1957). The very few cases of OPIDP reported in young individuals indicate that they recover completely, even from severe lower and upper limb involvement (Senanayake, 1981; Goldenstein et al., 1988). At onset, the electrophysiological examination is characterized by reduced amplitude of the compound muscle potential after supramaximal stimulation of motor nerves, increased distal latencies, and normal or slightly reduced nerve conduction velocities. Over a few days, unexcitability of the nerve ensues in severe cases. Signs of denervation of the affected muscles with increased insertional activity, spontaneous activity (fibrillation potentials and positive sharp waves), and reduced interference pattem are observed at electromyography (Lotti et al., 1986; Sevim et al., 2003; Vasconcellos et al., 2002; McConnell et al., 1999; Senanayake and Johnson, 1982; Wadia et al., 1985; Vasilescu and Florescu, 1980; Shiraishi et al., 1983; Vasilescu et al., 1984; Moretto and Lotti, 1998). These findings are consistent with distal axonal degeneration, observed when biopsies of the sural nerve were performed (Shiraishi et al., 1983; Vasilescu et al., 1984; Jedrzejowska et al., 1980; De Kort et al., 1986; Lotti et al., 1986; Chuang et al., 2002). The very few data available on spinal cord histopathology show a distribution of the lesions similar to that seen in animals, with involvement of the distal pyramidal tract and the proximal columns of Goll (fasciculus gracili medullae spinalis) (Aring, 1942, as reported by Susser and Stein, 1957). Observational studies aimed at detecting mild peripheral neuropathy or changes in peripheral nerve functions have been performed on individuals with varying long-term, lowlevel exposures to OPs, including different occupational exposures such as those occurring in sheep dip farmers and exposures during the first Gulf War. These studies were reviewed by Lotti (2002b). It was concluded that they suffered from a number of limitations. For instance, they did not accurately assess exposure, and reported changes in peripheral nerves were usually mild and inconsistent, sometimes reversible, and sometimes apparently irreversible because they were observed long after cessation of exposure.

365

Understanding these changes is difficult because of the lack of histopathology, follow-up data, and an experimental model for such peripheral nerve changes that seem different from classic OPIDE In addition, electrophysiological results were usually examined together on a group basis and correlation with clinical data was almost always missing. Finally, since these pesticides are far better inhibitors of AChE than NTE, they are expected to cause peripheral neuropathy at doses that inevitably cause cholinergic toxicity, irrespective of the type of exposure.

VI. PROMOTION OF OPIDP AND OTHER AXONOPATHIES IN EXPERIMENTAL ANIMALS Certain nonneuropathic OPs and CMs, as well as other esterase inhibitors such as sulfonyl fluorides, exacerbate toxic and traumatic axonopathies when administered in combination (Pope and Padilla, 1990; Lotti et al., 1991; Moretto et al., 1992b, 1993; Johnson and Read, 1993). This phenomenon was called promotion of axonopathies when it was first observed while studying OPIDP (Pope and Padilla, 1990; Lotti et al., 1991). Several of these compounds are NTE inhibitors as well, and they protect from OPIDP when given before and promote OPIDP when given after the neuropathic OE However, other inhibitors of esterases, but not of NTE (e.g., paraoxon and various sulfonyl fluorides), did not promote OPIDP when given at maximum tolerated doses (Lotti et al., 1991; Osman et al., 1996). The type and distribution of histopathological lesions in promoted animals did not differ from those observed in animals affected by classical OPIDE This indicates that promoters exacerbate existing damage and do not affect areas, neurons, or axons that are not typically involved in OPIDP (Pope et al., 1992, 1993; Randall et al., 1997; Moretto et al., 2001). A number of observations led to the hypothesis that promotion may involve the compensation/repair mechanism(s) of the nervous system (Lotti, 1995). For instance, promotion is not specific to OPIDP since other axonopathies of toxic (e.g., 2,5-hexanedione) (Moretto et al., 1992b) as well as traumatic origin (Moretto et al., 1993) were also promoted by PMSE Promotion was found to be less effective in chicks, in which repair mechanisms are believed to be more efficient (Peraica et al., 1993). Moreover, since promotion also occurred when the promoter was given up to a few days before the toxic or traumatic neuropathic insult, the mechanism involved in promotion is not activated by the neuropathic lesion/insult to the nerve but appears to be already present in healthy axons (Moretto et al., 1993, 1994). The molecular target of promotion is unknown, but there is evidence that it is not NTE (Moretto et al., 1994; Lotti et al., 1995). Nevertheless, all promoters tested so far are NTE inhibitors (Lotti et al., 1995; Osman et al., 1996; Lotti and Moretto, 1999; Moretto et al., 2001). Initial experiments

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aimed at the identification of the target of promotion searched for PV esterase activities in peripheral nerve after exclusion of NTE but were not successful (Milatovic et al., 1997). Upon reconsideration of the operational definition of NTE, a PV esterase activity with a sensitivity to inhibition by mipafox lower (IC50, --200 IxM) than that of NTE (IC50, -7 ~ , was found and called M200. Inhibition of this activity correlated with promotion when several compounds were tested (Moretto et al., 1996). This activity had approximately the same sensitivity to inhibition by mipafox of a soluble activity in the peripheral nerves identified by Escudero and Vilanova (1997) by separation with a Sephacryl S-300 column. This activity was also inhibited by promoters (Nicolli et al., 2002). Further purification of this fraction by ion-exchange chromatography identified a fraction apparently containing one 80-kDa protein with esteratic activity that, when tested with a limited number of compounds, was inhibited by promoters (Nicolli et aL, 2002). A mechanism different from that of typical OPIDP was suggested to explain the neuropathy occurring after promotion because the pattern of neurofilament subunit alterations found in animals, in which OPIDP was promoted (Xie et al., 2001, 2002), was different from that observed in animals with typical OPIDP (Gupta et al., 2000). However, because of the lack of concurrent controls, it is difficult to ascertain if such differences between promoted and classical OPIDP are real, considering that changes were often erratic over time and it was difficult to distinguish whether they were causally related or secondary to neuropathy.

References Abdelsalam, E. B. (1999). Neurotoxic potential of six organophosphorus compounds in adult hens. Vet. Hum. Toxicol. 41, 290-292. Abou-Donia, M. B. (2003). Organophosphorus ester-induced chronic neurotoxicity. Arch. Environ. Health 58, 484-497. Abou-Donia, M. B., Viana, M. E., Gupta, R. E, and Anderson, J. K. (1993). Enhanced calmodulin binding concurrent with increased kinase-dependent phosphorylation of cytoskeletal protein following a single subcutaneous injection of diisopropyl phosphorofluoridate in hens. Neurochem. Int. 22, 165-173. Aiuto, L. A., Pavlakis, S. G., and Boxer, R. A. (1993). Lifethreatening organophosphate-induced delayed polyneuropathy in a child after accidental chlorpyrifos ingestion. J. Pediatr. 122, 658-660. Akassoglou, K., Malester, B., Xu, J., Tessarollo, L., Rosenbluth, J., and Chao, M.V. (2004). Brain-specific deletion of neuropathy target esterase/swisscheese results in neurodegeneration. Proc. Natl. Acad. Sci. USA 101, 5075-5080. Aldridge, W. N., and Reiner, E. (1972) Enzyme Inhibitors as Substrates: Interactions of Esterases with Esters of Organophosphorus and Carbamic Acids. North-Holland,

Amsterdam. Alonso, J. L., Atalla, A., Cavaliere, M. J., Gagioti, S. M., and Lorenti, M. A. (1983). Polineuropatia por parathion. Arq. Neuro-Psiq. 41, 292-308. [in Portuguese]

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CHAPTER 25 9 Delayed Neuropathy

glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in the central nervous system of hens treated with diisopropylphosphorofluoridate (DFP). Neurochem. Int. 40, 371-379. Daugherty, W., Biles, R., Jortner, B., and Ehrich, M. (1996). Subchronic delayed neurotoxicity evaluation of jet engine lubricants containing phosphorus additives. Fundam. Appl. Toxicol. 32, 244-249. De Haro, L., Arditti, J., Davide, J. M., and Jouglard, J. (1999). Intoxication au methamidophos: Toxicit6 neurologiqu6 immediate et retard6e; Apropos de deux observations. Acta Clin. Belgica. (Suppl.)l, 64-67. [in French] De Jager, A. E. J., van Weerden, T. W., Houthoff, H. J., and De Monchy, J. G. (1981). Polyneuropathy after massive exposure to parathion. Neurology 31, 603-605. De Kort, W. L. A. M., Savelkoul, T. J. F., Sindram, J. W., and Jennekens, E G. I. (1986). Delayed neurotoxicity'na intoxicatie met organofosforverbindingen. Ned. Tijdscher. Geneesked. 130, 1896-1898. [in Dutch] De Silva, H. J., Sanmugtanathan, P. S., and Senanayake, N. (1994). Isolated bilateral recurrent laryngeal nerve paralysis: A delayed complication of organophosphorus poisoning. Hum. Exp. Toxicol. 13, 171-173. Dickoff, D. J., Gerber, O., and Turovsky, Z. (1987). Delayed neurotoxicity after ingestion of carbamate pesticide. Neurology 37, 1229-1231. Dive, A., Mahieu, R., van B inst, R., Hassoun, A., Lison, D., De Bisschop, H., Nemery, B., and Lauwerys, R. (1994). Unusual manifestations after malathion poisoning. Hum. Exp. Toxicol. 13, 271-274. E1-Fawal, H. A. N., Jortner, B. S., and Ehrich, M. (1989). Effect of verapamil on organophosphorus-induced delayed neuropathy in hens. Toxicol. Appl. Pharmacol. 97, 500-511. Eray, D., Kamer, U. M., and Ozden, A. (1995). Organophosphateinduced delayed polyneuropathy. J. Trop. Ped. 41, 189. [Letter] Escudero, M. A., and Vilanova, E. (1997). Purification and characterization of naturally soluble neuropathy target esterase from chicken sciatic nerve by HPLC and Western blot. J. Neurochem. 69, 1-8. Fisher, J. R. (1977). Guillain-Barr~ syndrome following organophosphate poisoning. J. Am. Med. Assoc. 238, 1950-1951. Forshaw, P. J., Atkins, J., Ray, D. E., and Glynn, P. (2001). The catalytic domain of human neuropathy target esterase mediates an organophosphate-sensitive ionic conductance across liposome membranes. J. Neurochem. 79, 400-406. Fowler, M. J., Flaskos, J., Mclean, W. G., and Hargreaves, A. J. (2001). Effects of neuropathic and non-neuropathic isomers of tricresyl phosphate and their microsomal activation on the production of axon-like processes by differentiating mouse N2a neuroblastoma cells. J. Neurochem. 76, 671-678. Francis, B. M., Metcalf, R. L., and Hansen, L. G. (1985). Toxicity of organophosphorus esters to laying hens after oral and dermal administration. J. Environ. Sci. Health B 20, 73-95. Funk, K. A., Henderson, J. D., Liu, C. H., Higgins, R. J., and Wilson, B. W. (1994). Neuropathology of organophosphateinduced delayed neuropathy (OPIDN) in young chicks. Arch. Toxicol. 68, 308-316. Glynn, P. (1999). Neuropathy target esterase. Biochem. J. 344, 625-631. Glynn, P., Holton, J. L., Nolan, C. C., Read, D. J., Brown, L., Hubbard, A., and Cavanagh, J. B. (1998). Neuropathy target

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