Neuropathologic effects of phenylmethylsulfonyl fluoride (PMSF)-induced promotion and protection in organophosphorus ester-induced delayed neuropathy(OPIDN) in hens

The serine/cysteine protease inhibitor phenylmethylsulfonyl fluoride (PMSF) has been used both to promote and to protect against neuropathic events of organophosphorus-induced delayed neuropathy IOPIDN) in hens (Veronesi and Padilla, 1985; Pope and Padilla, 1990; Lotti et al., 1991; Pope et al., 199 3; Randall et al., 1997). This study is the first to expand upon this work by using high resolution microscopy provided by epoxy resin embedding and t hin sectioning to evaluate neuropathological manifestations of promotion an d protection, and to correlate them with associated clinical modifications. To evaluate dose-related effects of OPIDN, single phenyl saligenin phospha te (PSP) dosages of 0.5, 1.0, or 2.5 mg/kg were administered to adult hens. PMSF (90 mg/kg) was given either 4 hours after (for promotion) or 12 hours prior To (for protection) PSP administration. Clinical signs and pathologi c changes in the biventer cervicis nerve, which is uniquely sensitive to OP IDN (N-Fawal et al., 1988), were monitored. PSP alone, 2.5 mg/kg, caused se vere OPIDN (terminal clinical score 7.5 +/- 1.0 [0-8 scale]; neuropathology score 2.7 +/- 0.3 [0-4 scale, based on myelinated fiber degeneration]). PM SF given 12 hours prior to PSP gave complete protection (clinical and neuro pathology scores of 0, p<0.0001 compared to PSP alone). Signs and lesions o f OPIDN were absent following 0.5 mg/kg PSP alone, but PMSF given 4 hours a fter PSP potentiated its neurotoxic effects tall hens had clinical scores o f 4.0 and the average neuropathology score was 3.5 +/- 0.3; p<0.0001 compar ed to PSP alone). Although quantitative differences were noted, qualitative differences among nerves from hens with OPIDN were not evident, either wit h light or electron microscopy At the time of sacrifice, there was a statis tically linear relationship (r(2) = 0.76) between the clinical scores on th e last day of observation and the neuropathology scores (p<0.0001). This st udy demonstrates that the degree of peripheral nerve myelinated fiber degen eration correlates with clinical deficits in PMSF-induced potentiation of a nd protection against OPIDN. (C) 1999 Inter Press, Inc.