title: In vitro study of the neuropathic potential of the organophosphorus compounds fenamiphos and profenofos: Comparison with mipafox and paraoxon.
abstract: Organophosphorus-induced delayed neuropathy (OPIDN) is a central-peripheral distal axonopathy that develops 8-14 days after poisoning by a neuropathic organophosphorus compound (OP). Several OPs that caused OPIDN were withdrawn from the agricultural market due to induction of serious delayed effects. Therefore, the development of in vitro screenings able to differentiate neuropathic from non-neuropathic OPs is of crucial importance. Thus, the aim of this study was to evaluate the differences in the neurotoxic effects of mipafox (neuropathic OP) and paraoxon (non-neuropathic OP) in SH-SY5Y human neuroblastoma cells, using the inhibition and aging of neuropathy target esterase (NTE), inhibition of acetylcholinesterase (AChE), activation of calpain, neurite outgrowth, cytotoxicity and intracellular calcium as indicators. Additionally, the potential of fenamiphos and profenofos to cause acute and/or delayed effects was also evaluated. Mipafox had the lowest IC50 and induced the highest percentage of aging of NTE among the OPs evaluated. Only mipafox was able to cause calpain activation after 24 h of incubation. Concentrations of mipafox and fenamiphos which inhibited at least 70% of NTE were also able to reduce neurite outgrowth. Cytotoxicity was higher in non-neuropathic than in neuropathic OPs while the intracellular calcium levels were higher in neuropathic than in non-neuropathic OPs. In conclusion, the SH-SY5Y cellular model was selective to differentiate neuropathic from non-neuropathic OPs; fenamiphos, but not profenofos presented results compatible with the induction of OPIDN.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP, USP, Avenida do Café s/n, Monte Alegre, 14040-903 Ribeirão Preto, SP, Brazil; Departamento de Farmácia, Instituto de Ciências da Saúde, Universidade Federal de Mato Grosso - ICS/UFMT/CUS, Sinop, MT, Brazil. Electronic address: glemerick@yahoo.com.br.
authors.forename: Guilherme L
authors.initials: GL
authors.lastname: Emerick
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP, USP, Avenida do Café s/n, Monte Alegre, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Laís S
authors.initials: LS
authors.lastname: Fernandes
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP, USP, Avenida do Café s/n, Monte Alegre, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Eloísa Silva
authors.initials: ES
authors.lastname: de Paula
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP, USP, Avenida do Café s/n, Monte Alegre, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Barbosa
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP, USP, Avenida do Café s/n, Monte Alegre, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Neife Aparecida Guinaim
authors.initials: NA
authors.lastname: dos Santos
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP, USP, Avenida do Café s/n, Monte Alegre, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Antonio Cardozo
authors.initials: AC
authors.lastname: dos Santos
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D016501:Neurites / Q000187:drug effects; D020258:Neurotoxicity Syndromes; D009943:Organophosphorus Compounds / Q000633:toxicity*
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009943:Organophosphorus Compounds; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase; D002154:Calpain; D002118:Calcium
keywords: Acetylcholinesterase; Calcium; Cytotoxicity; Neurite extension; Neuropathy target esterase; Organophosphorus pesticides