| Grant number: | 13/26906-6 |
| Support Opportunities: | Regular Research Grants |
| Start date: | November 01, 2014 |
| End date: | April 30, 2017 |
| Field of knowledge: | Health Sciences - Pharmacy - Toxicological Analysis |
| Principal Investigator: | Antonio Cardozo dos Santos |
| Grantee: | Antonio Cardozo dos Santos |
| Host Institution: | Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil |
| City of the host institution: | Ribeirão Preto |
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)
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