Early effects of neuropathy-inducing organophosphates on in vivo concentrations of three neurotrophins.
Exposure to OP compounds that inhibit neurotoxic esterase (NTE) induces a delayed neuropathy (OPIDN) characterized by Wallerian-like degeneration of long axons in certain animals, including humans. Pope et al. (Toxicol. Lett. 75:111-117, 1995) found that neurite outgrowth occurred following the addition of spinal cord extracts from chickens with active OPIDN to neuroblastoma cells, suggesting growth factor expression during the neuropathy. We hypothesized that, shortly after exposure to a neuropathic OP compound, the central nervous system (CNS) attempts to recover from the toxic insult through upregulation of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) in susceptible regions of the nervous system. We hypothesized that such upregulation is transient and cannot be sustained. To test this hypothesis, we exposed 10-week-old chickens to a neuropathic OP compound (PSP, 2.5 mg/kg), a non-neuropathic OP compound (paraoxon, 0.10 mg/kg), and vehicle (DMSO, 0.5 ml/kg) intramuscularly. By day 8, all PSP-treated birds demonstrated clinical signs of OPIDN. We sacrificed chickens by pentobarbital overdose at 4, 8, 24, and 48 hours, and 5 and 10 days post-exposure and confirmed NTE inhibition in birds treated with PSP 4 and 24 hours earlier. Enzyme-linked immunosorbant assays indicated that NGF, BDNF, and NT-3 are found in chicken lumbar spinal cord after exposure to a neuropathic OP compound. However, exposure to the neuropathic OP compound, PSP, did not preferentially elevate levels of NGF, BDNF, and NTE compared to the non-neuropathic OP compound, paraoxon. This suggests that these neurotrophins alone do not contribute to a sustained regenerative effort in the CNS.
Pomeroy-Black
M J
MJ
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, 1 Duckpond Drive, Blacksburg, VA 24061, USA. marion@vt.edu
Jortner
B S
BS
Ehrich
M F
MF
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002645:Chickens; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D009416:Nerve Regeneration; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010261:Paraoxon / Q000633:toxicity; D014855:Wallerian Degeneration / Q000139:chemically induced* / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D002800:Cholinesterase Inhibitors; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D009943:Organophosphorus Compounds; C046357:phenylsaligenin cyclic phosphate; D020932:Nerve Growth Factor; D010261:Paraoxon