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In vitro study of the mechanisms of neurotoxicity of the organophosphate trichlorfon: strategies for neuroprotection

Grant number: 12/16319-3
Support type:Scholarships in Brazil - Master
Effective date (Start): November 01, 2012
Effective date (End): July 31, 2014
Field of knowledge:Biological Sciences - Pharmacology - Toxicology
Principal researcher:Antonio Cardozo dos Santos
Grantee:Lais da Silva Fernandes
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The pesticide trichlorfon (dimethyl 2,2,2-trichloro-1-hydroxyethyl Phosphonate) has been widely used in agricultural production and also the control of vectors that transmit various diseases due to its inhibitory effect of acetylcholinesterase (AChE) in insects. However, the toxicity of organophosphate (OP) is not limited to insects, irreversible effects can be induced in humans, such as neuropathy induced Delayed Organophosphate (NRIOP). Due to the large number of poisonings by these compounds, it is necessary to elucidate the mechanism of cell degeneration which characterizes the NRIOP irreversible. It is known that after a OP neuropathic poisoning occurs about 70-80% and aging of inhibition known as an esterase capable esterase neuropathy (ESNp), which triggers a cascade of events leading to Wallerian-type axonal degeneration. The neuropathy is characterized by a distal axon degeneration of the central and peripheral nervous system, and is 1-4 weeks after exposure. Previous studies have linked the NRIOP to a decrease in extracellular calcium and increased activity of intracellular calcium-dependent protease (calpain), suggesting that inhibition after ESNp occurs cell influx of calcium. However, the mechanism and sequence of events involved in the development of NRIOP remain undefined. Thus, this study aims to evaluate the mechanism of toxicity of trichlorfon in cellular model of human neuroblastoma (SH-SY5Y), focusing on events associated with the influx of calcium into the cell. Furthermore, this also investigated the effects of compounds that can interfere with some point in this sequence of events, such as the inhibitor (III) and calpain inhibitor MDL 28,170 calcium channels of type T, amiloride, as possible protection strategies the NRIOP. Such information will be helpful in better understanding of mechanisms of neurotoxicity of OPs, as well as the development of future therapeutic approaches for NRIOP. (AU)

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FERNANDES, LAIS SILVA; DOS SANTOS, NEIFE APARECIDA G.; EMERICK, GUILHERME LUZ; DOS SANTOS, ANTONIO CARDOZO. The Antidiabetic Drug Liraglutide Minimizes the Non-Cholinergic Neurotoxicity of the Pesticide Mipafox in SH-SY5Y Cells. NEUROTOXICITY RESEARCH, v. 35, n. 1, p. 150-159, JAN 2019. Web of Science Citations: 4.
FERNANDES, LAIS SILVA; EMERICK, GUILHEMIE LUZ; FERREIRA, RAFAELA SCALCO; DOS SANTOS, NEIFE APARECIDA G.; DOS SANTOS, ANTONIO CARDOZO. High concentration of trichlorfon (1 mM) disrupts axonal cytoskeleton and decreases the expression of plasticity-related proteins in SH-SY5Y cells. TOXICOLOGY IN VITRO, v. 39, p. 84-92, MAR 2017. Web of Science Citations: 3.
FERNANDES, LAIS SILVA; DOS SANTOS, NEIFE APARECIDA G.; EMERICK, GUILHERME LUZ; DOS SANTOS, ANTONIO CARDOZO. L- and T-type calcium channel blockers protect against the inhibitory effects of mipafox on neurite outgrowth and plasticity-related proteins in SH-SY5Y cells. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES, v. 80, n. 19-21, SI, p. 1086-1097, 2017. Web of Science Citations: 3.
EMERICK, GUILHERME L.; FERNANDES, LAIS S.; DE PAULA, ELOISA SILVA; BARBOSA, JR., FERNANDO; GUINAIM DOS SANTOS, NEIFE APARECIDA; DOS SANTOS, ANTONIO CARDOZO. In vitro study of the neuropathic potential of the organophosphorus compounds fenamiphos and profenofos: Comparison with mipafox and paraoxon. TOXICOLOGY IN VITRO, v. 29, n. 5, p. 1079-1087, AUG 2015. Web of Science Citations: 7.
FERNANDES, LAIS S.; EMERICK, GUILHERME L.; DOS SANTOS, NEIFE APARECIDA G.; DE PAULA, ELOISA SILVA; BARBOSA, JR., FERNANDO; DOS SANTOS, ANTONIO CARDOZO. In vitro study of the neuropathic potential of the organophosphorus compounds trichlorfon and acephate. TOXICOLOGY IN VITRO, v. 29, n. 3, p. 522-528, APR 2015. Web of Science Citations: 15.

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