title: Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds.
abstract: Inhibition and aging of neuropathy target esterase (NTE) by neuropathic organophosphorus (OP) compounds triggers OP compound-induced delayed neuropathy (OPIDN), whereas inhibition of acetylcholinesterase (AChE) produces cholinergic toxicity. The neuropathic potential of an OP compound is defined by its relative inhibitory potency toward NTE vs. AChE assessed by enzyme assays following dosing in vivo or after incubations of direct-acting compounds or active metabolites with enzymes in vitro. The standard animal model of OPIDN is the adult hen, but its large size and high husbandry costs make this species a burdensome model for assessing neuropathic potential. Although the mouse does not readily exhibit clinical signs of OPIDN, it displays axonal lesions and expresses brain AChE and NTE. Therefore, the present research was performed as a further test of the hypothesis that inhibition of mouse brain AChE and NTE could be used to assess neuropathic potential using mouse brain preparations in vitro or employing mouse brain assays following dosing of OP compounds in vivo. Excellent correlations were obtained for inhibition kinetics in vitro of mouse brain enzymes vs. hen brain and human recombinant enzymes. Furthermore, inhibition of mouse brain AChE and NTE after dosing with OP compounds afforded ED(50) ratios that agreed with relative inhibitory potencies assessed in vitro. Taken together, results with mouse brain enzymes demonstrated consistent correspondence between in vitro and in vivo predictors of neuropathic potential, thus adding to previous studies supporting the validity of a mouse model for biochemical assessment of the ability of OP compounds to produce OPIDN.
authors.affiliation: Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Galina F
authors.initials: GF
authors.lastname: Makhaeva
authors.forename: Elena V
authors.initials: EV
authors.lastname: Rudakova
authors.forename: Nichole D
authors.initials: ND
authors.lastname: Hein
authors.forename: Olga G
authors.initials: OG
authors.lastname: Serebryakova
authors.forename: Nadezhda V
authors.initials: NV
authors.lastname: Kovaleva
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Boltneva
authors.forename: John K
authors.initials: JK
authors.lastname: Fink
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Richardson
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002645:Chickens; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000209:etiology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D013045:Species Specificity
chemical_list: D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase
keywords: acetylcholinesterase (AChE); mouse; neuropathy target esterase (NTE); organophosphorus (OP) compounds; organophosphorus compound-induced delayed neuropathy (OPIDN)