Possible involvement of a neurotrophic factor during the early stages of organophosphate-induced delayed neurotoxicity.
Little is known regarding early biochemical events in organophosphate-induced delayed neurotoxicity (OPIDN) except for the essential inhibition of neurotoxic esterase (NTE). We hypothesized that a trophic factor may be produced in situ shortly after exposure to the OP which participates in the progression of OPIDN. To bioassay for such a growth-modulating factor(s), we treated chickens with the neuropathic agents diisopropylfluorophosphate (DFP) or cyclic phenyl saligenin phosphate (PSP), with or without phenylmethylsulfonyl fluoride (PMSF, a chemical which markedly modifies OPIDN). Soluble extracts of cervical spinal cord (a region of the nervous system which degenerates with OPIDN) were collected 24 h later and these were incubated with human neuroblastoma SY5Y cells in culture. The cells were allowed to grow for another 6 days and observed for changes in morphology and growth. After 3 days in culture, tissue extracts from OP-treated chickens caused SY5Y cells to begin to elongate and extend processes (neurites), similar to cells treated with nerve growth factor (1 microgram/ml). Extracts from chickens not receiving OP had no or minimal effects on cell morphology. In addition, extracts from chickens in which OPIDN was prevented by pretreatment with PMSF did not cause the marked extension of cell processes exhibited after exposure of SY5Y cells to extracts from chickens given regimens known to cause OPIDN. In parallel-treated animals. DFP and PSP caused clinical dysfunction characteristic of OPIDN, PMSF posttreatment markedly amplified the clinical deficits and PMSF pretreatment prevented OPIDN. In vivo DFP treatment also caused a marked reduction in the activity of the growth-related enzyme ornithine decarboxylase (ODC) in spinal cord but DFP was without effect on ODC activity in vitro (up to 1 mM final concentration). Characterization of this growth-modulating factor(s) may aid in the elucidation of pathological mechanisms of OPIDN.
Pope
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C
Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209-0470.
diLorenzo
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Ehrich
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M
D000818:Animals; D002645:Chickens; D005260:Female; D006801:Humans; D007531:Isoflurophate / Q000633:toxicity; D008297:Male; D009414:Nerve Growth Factors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009420:Nervous System / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured
D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009943:Organophosphorus Compounds; D007531:Isoflurophate; D010664:Phenylmethylsulfonyl Fluoride; D009955:Ornithine Decarboxylase