Cisplatin-induced peripheral sensory neuropathy: Study of the mechanisms of neurotoxicity of cisplatin and neuroprotection of caffeic acid phenethyl ester (CAPE) in PC-12 cells

• Grant number: 17/09332-7
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2017
• End date: April 30, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Toxicology
• 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

Abstract

The clinical use of cisplatin (cis-diaminochloroplatin II) is limited by its severe adverse effects, including neurotoxicity. Platinum compounds accumulate in sensory neurons, causing loss of myelinated fibers, axonal degeneration, and neuronal dysfunction. The main clinical manifestation is peripheral sensory neuropathy characterized by loss of reflexes, paresthesia in the extremities of lower limbs and severe sensory ataxia. To date, no effective prevention or treatment strategy has been developed. Mechanisms of axonal degeneration and regeneration are poorly understood and their modulation may be a neuroprotection strategy. Studies have shown that (i) neurotrophin deprivation induces axonal degeneration and (ii) administration of exogenous neurotrophic factors promotes axonal regeneration in both the central and peripheral nervous systems. Caffeic acid phenethyl ester (CAPE) is a bioactive component of bee propolis and, according to our studies, has a neurotrophic and neuroprotective effect in models (in vitro and in vivo) associated with Parkinson's disease. Thus, it is possible that CAPE may also play a beneficial role in cisplatin-induced neuropathy, a hypothesis not yet investigated in the scientific literature. In this study, we will evaluate the neuroprotective effects of CAPE, focusing on neuritogenesis and neurotrophic signaling pathways, using PC-12 cells exposed to cisplatin. PC-12 cells are an appropriate neuronal model for evaluating cell differentiation, because they express trkA receptors and respond to NGF by ceasing proliferation, emitting neurites (precursors of axons and dendrites) and acquiring characteristics similar to those of sympathetic neurons. The following parameters will be evaluated: cellular viability, cellular bioenergetics (glucose uptake, ATP efflux), reactive oxygen species and induction of neuritogenesis, the latter in the presence and absence of pharmacological inhibitors of neurotrophin-activated signaling pathways (MAPK / ERK and PI3K / AKT). Furthermore, the expression of neuroplasticity marker proteins (GAP-43, Synapsin, synaptophysin, neurofilament) and cytoskeleton proteins (F-actin and ²-tubulin) important for synaptic plasticity, will be evaluated. Additionally, the induction of neuritogenesis in a SH-SY5Y-neuronal model, which express a different phenotype for neurotrophic receptors (trkB / BDNF) will be evaluated. The results of this study will contribute to a better understanding of axonal degeneration / regeneration mechanisms and to the development of strategies for the prevention and / or treatment of peripheral sensory neuropathy induced by cisplatin. (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)

GUINAIM DOS SANTOS, NEIFE APARECIDA; FERREIRA, RAFAELA SCALCO; DOS SANTOS, ANTONIO CARDOZO. Overview of cisplatin-induced neurotoxicity and ototoxicity, and the protective agents. Food and Chemical Toxicology, v. 136, FEB 2020. (17/09332-7)

FERREIRA, RAFAELA SCALCO; GUINAIM DOS SANTOS, NEIFE APARECIDA; BERNARDES, CAROLINA P.; SISTI, FLAVIA MALVESTIO; AMARAL, LILIAN; FONTANA, ANDREIA C. K.; DOS SANTOS, ANTONIO CARDOZO. Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity by Activating the AMPK/SIRT1, MAPK/Erk, and PI3k/Akt Signaling Pathways. NEUROTOXICITY RESEARCH, v. 36, n. 1, p. 175-192, JUL 2019. (17/09332-7)

FERREIRA, RAFAELA SCALCO; GUINAIM DOS SANTOS, NEIFE APARECIDA; MARTINS, NADIA MARIA; FERNANDES, LAIS SILVA; DOS SANTOS, ANTONIO CARDOZO. Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells from Cisplatin-Induced Neurotoxicity by Activating the NGF-Signaling Pathway. NEUROTOXICITY RESEARCH, v. 34, n. 1, p. 32-46, JUL 2018. (17/09332-7)