Potentiation of Organophosphorus Compound-Induced Delayed Neurotoxicity (Opidn) in the Central and Peripheral Nervous System of the Adult Hen: Distribution of Axonal Lesions

Abstract

Clinical manifestations of mild organophosphorus compound-induced delayed neurotoxicity (OPIDN) produced by diisopropylphosphorofluoridate (DFP) in adult hens are potentiated by posttreatment with phenylmethanesulfonyl fluoride (PMSF). The purpose of this study was to assess whether potentiation of mild OPIDN produces a pattern of axonal lesions in the central and peripheral nervous system similar to that seen in severe OPIDN. Groups of 6 hens each were given the following priming/challenge doses sc at 0 and 4 h, respectively: 0.20 ml/kg corn oil/0.50 ml/kg glycerol formal (GF) (control); 0.50 mg/kg DFP/GF (low-dose DFP); 0.50 mg/kg DFP/60 mg/kg PMSF (potentiated DFP); 60 mg/kg PMSF/GF (PMSF alone); 60 mg/kg PMSF/1.5 mg/kg DFP (protected DFP); and 1.5 mg/kg DFP/GF (high-dose DFP). Two hens from each group were used to assay brain neurotoxic esterase (NTE) 24 h after the challenge dose, and the remaining hens were scored for deficits in walking, standing, and perching ability on d 18. Three hens from each group were perfusion-fixed on d 22 and neural tissues were prepared for histologic evaluation. DFP and/or PMSF caused > 88% brain NTE inhibition in all treated groups, compared to control. Protected DFP yielded no clinical deficits and a distribution and frequency of axonal lesions similar to control. PMSF alone produced a small increase in the frequency of lesions in the cervical spinal cord and peripheral nerves compared to control. Low-dose DFP caused minimal ataxia and increased frequency of axonal lesions in dorsal and lateral cervical spinal cord, ventral lumbar spinal cord, and inferior cerebellar peduncles (ICP) compared to control. Potentiated DFP and high-dose DFP produced maximal ataxia and essentially identical increases in the frequency of lesions in dorsal and ventral thoracic spinal cord, lateral lumbar spinal cord, and peripheral nerves compared to low-dose DFP. The results indicate that PMSF potentiation of mild OPIDN induced in adult hens by low-dose DFP results in an overall pattern of axonal degeneration like that produced by a threefold higher dose of DFP alone, and support the hypothesis that potentiation causes an increase in the frequency of axonal lesions in central and peripheral loci normally affected by OPIDN.

Neuropathy Target Esterase

“…The possible relevance of any of these soluble enzymes to either initiation of OPIDN or its potentiation (elicitation of OPIDN by nonneuropathic NTE inhibitors after prior treatment with a near-threshold dose of a neuropathic NTE inhibitor -a phenomenon discussed in Chapter 69, in which it is called promotion) (Randall et al, 1997) requires evaluation by structure-activity relationship (SAR) studies using tissue from hens dosed with a battery of neuropathic and nonneuropathic OP compounds. To date, studies in vitro with the soluble enzymes discourage an association because sensitivity to mipafox in vitro is so considerable (20-min I 50  0.1 M compared with 7 M for NTE) that one might expect that such activities would be fully inhibited in vivo at doses that would scarcely affect NTE and would be well below the neuropathic or promoting dose.…”

Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity

“…The neuropathies in hens arising from organophosphate inhibition of NTE cause wallerian axonal degeneration and show vacuolation and neuronal swelling over a period of 1-3 weeks 40,41 . Although the hen is the preferred model for OPIDN studies, there is growing evidence that this model may not properly estimate the risk of organophosphate exposure in humans and other mammals 42 and does not address short-and mediumterm toxicities of organophosphates or non-neuropathy longterm sequelae.…”

Organophosphorus-Induced Delayed Neuropathy

“…Promotion or potentiation, in which administration of certain NTE inhibitors after neuropathy-inducing OP compounds will initiate or exacerbate clinical manifestations and nervous system lesions of OPIDN, has been reported in many studies Lotti, 2002;Lotti and Moretto, 1999;Massicotte et al, 1999;Moretto et al, 2005;Pope and Padilla, 1990;Pope et al, 1992Pope et al, , 1995Randall et al, 1997). The exacerbation of OPIDN appears to be due to a quantitative rather than qualitative difference, as observed in hens given several different OP compounds (e.g., DFP, DBD-CVP, and PSP) and several different NTE inhibitors, with phenyl methanesulfonyl fluoride being used most often (Massicotte et al, 1999;Moretto et al, 1992a;Osman et al, 1996;Peraica et al, 1995;Randall et al, 1997).…”

“…The exacerbation of OPIDN appears to be due to a quantitative rather than qualitative difference, as observed in hens given several different OP compounds (e.g., DFP, DBD-CVP, and PSP) and several different NTE inhibitors, with phenyl methanesulfonyl fluoride being used most often (Massicotte et al, 1999;Moretto et al, 1992a;Osman et al, 1996;Peraica et al, 1995;Randall et al, 1997). To date, all promotors of OPIDN are NTE inhibitors, yet most are those that do not lose a side group after attachment to the enzyme (in other words, the promoter-enzyme complex does not have to age) .…”