title: Non-cytotoxic Concentration of Cisplatin Decreases Neuroplasticity-Related Proteins and Neurite Outgrowth Without Affecting the Expression of NGF in PC12 Cells.
abstract: Cisplatin is the most effective and neurotoxic platinum chemotherapeutic agent. It induces a peripheral neuropathy characterized by distal axonal degeneration that might progress to degeneration of cell bodies and apoptosis. Most symptoms occur nearby distal axonal branches and axonal degeneration might induce peripheral neuropathy regardless neuronal apoptosis. The toxic mechanism of cisplatin has been mainly associated with DNA damage, but cisplatin might also affect neurite outgrowth. Nevertheless, the neurotoxic mechanism of cisplatin remains unclear. We investigated the early effects of cisplatin on axonal plasticity by using non-cytotoxic concentrations of cisplatin and PC12 cells as a model of neurite outgrowth and differentiation. PC12 cells express NGF-receptors (trkA) and respond to NGF by forming neurites, branches and synaptic vesicles. For comparison, we used a neuronal model (SH-SY5Y cells) that does not express trkA nor responds to NGF. Cisplatin did not change NGF expression in PC12 cells and decreased neurite outgrowth in both models, suggesting a NGF/trkA independent mechanism. It also reduced axonal growth (GAP-43) and synaptic (synapsin I and synaptophysin) proteins in PC12 cells, without inducing mitochondrial damage or apoptosis. Therefore, cisplatin might affect axonal plasticity before DNA damage, NGF/trkA down-regulation, mitochondrial damage or neuronal apoptosis. This is the first study to show that neuroplasticity-related proteins might be early targets of the neurotoxic action of cisplatin and their role on cisplatin-induced peripheral neuropathy should be investigated in vivo.
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Prêto, São Paulo, Brazil.
authors.forename: Rafaela Scalco
authors.initials: RS
authors.lastname: Ferreira
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Prêto, São Paulo, Brazil.
authors.forename: Neife Aparecida Guinaim
authors.initials: NA
authors.lastname: Dos Santos
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Prêto, São Paulo, Brazil.
authors.forename: Nádia Maria
authors.initials: NM
authors.lastname: Martins
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Prêto, São Paulo, Brazil.
authors.forename: Laís Silva
authors.initials: LS
authors.lastname: Fernandes
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Prêto, São Paulo, Brazil. acsantos@fcfrp.usp.br.
authors.forename: Antonio Cardozo
authors.initials: AC
authors.lastname: Dos Santos
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019922:GAP-43 Protein / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D000071446:Neuronal Outgrowth / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects*; D016716:PC12 Cells; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism
chemical_list: D019922:GAP-43 Protein; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D002945:Cisplatin
keywords: Cisplatin; GAP-43; NGF; Neurite outgrowth; PC12 cells; SH-SY5Y cells; Synapsin I; Synaptophysin