Organophosphorus-induced delayed neuropathy: in vitro study of the mechanisms of neurotoxicity of trichlorfon and strategies of neuroprotection

• Grant number: 13/26906-6
• Support type: Regular Research Grants
• Duration: November 01, 2014 - April 30, 2017
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal researcher: Antonio Cardozo dos Santos
• Grantee: Antonio Cardozo dos Santos
• Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Organophosphate pesticides (OPs) are widely used in the chemical industry and agriculture worldwide. Many of them are potential causes of Organophosphate-induced delayed neuropathy (OPIDN), characterized by distal degeneration of axons of the central and peripheral nervous system (Wallerian-type degeneration). Our previous studies with OP have associated NRIOP with the increase in the intracellular calcium, increase of calpain activity and inhibition of neurite outgrowth, but the mechanisms responsible for these effects have not been elucidated yet. In the present study a cellular model of human neuroblastoma (SH-SY5Y) will be used to investigate the mechanisms of action of (i) a potentially neuropathic pesticide widely used in the country, trichlorfon (dimethyl 2,2,2 - trichloro hydroxyethyl phosphonate) and (ii) compounds capable of interfering with different events of these signaling pathways, and therefore with neuroprotective potential. The following parameters will be evaluated: NTE (neuropathy-target esterase) activity and aging , expression of calpain , intracellular calcium concentration, production of reactive oxygen species (ROS) and cellular bioenergetics (glucose) as well as the expression of proteins which modulate inflammation ( interleukins ) , neuritogenesis ( synaptophysin , synapsin I and GAP- 43) and apoptosis (caspase-3). Additionally, the possible neuroprotective effects of (i) MDL 28170 (calpain inhibitor III );( ii) amiloride ( inhibitor of type T calcium channels) and ( iii ) liraglutide (agonist of GLP- 1 or Glucagon-like peptide 1) will be also investigated. Such information will be useful in better understanding the mechanisms of neurotoxicity of trichlorfon and neuropathic organophosphate (NOPs ) in general, as well as in the development of new therapeutic approaches to NRIOP. (AU)

Scientific publications

(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.