Neurotoxicity Research

, Volume 34, Issue 1, pp 32–46 | Cite as

Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells from Cisplatin-Induced Neurotoxicity by Activating the NGF-Signaling Pathway

  • Rafaela Scalco Ferreira
  • Neife Aparecida Guinaim dos Santos
  • Nádia Maria Martins
  • Laís Silva Fernandes
  • Antonio Cardozo dos Santos


Cisplatin is a highly effective chemotherapeutic drug that is toxic to the peripheral nervous system. Findings suggest that axons are early targets of the neurotoxicity of cisplatin. Although many compounds have been reported as neuroprotective, there is no effective treatment against the neurotoxicity of cisplatin. Caffeic acid phenethyl ester (CAPE) is a propolis component with neuroprotective potential mainly attributed to antioxidant and anti-inflammatory mechanisms. We have recently demonstrated the neurotrophic potential of CAPE in a cellular model of neurotoxicity related to Parkinson’s disease. Now, we have assessed the neurotrophic and neuroprotective effects of CAPE against cisplatin-induced neurotoxicity in PC12 cells. CAPE (10 μM) attenuated the inhibition of neuritogenesis and the downregulation of markers of neuroplasticity (GAP-43, synapsin I, synaptophysin, and 200-kD neurofilament) induced by cisplatin (5 μM). This concentration of cisplatin does not affect cell viability, and it was used in order to assess the early neurotoxic events triggered by cisplatin. When a lethal dose of cisplatin was used (IC50 = 32 μM), CAPE (10 μM) increased cell viability. The neurotrophic effect of CAPE is not dependent on NGF nor is it additive to the effect of NGF, but it might involve the activation of the NGF-high-affinity receptors (trkA). The involvement of other neurotrophin receptors such as trkB and trkC is unlikely. This is the first study to demonstrate the protective potential of CAPE against the neurotoxicity of cisplatin and to suggest the involvement of trkA receptors in the neuroprotective mechanism of CAPE. Based on these findings, the beneficial effect of CAPE on cisplatin-induced peripheral neuropathy should be further investigated.


Cisplatin Peripheral neurotoxicity CAPE Neuroprotection Neuritogenesis trkA receptors 



The authors would like to thank CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, grant number 140106/2015-4, Rafaela Scalco Ferreira) and FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, processo 2017/09332-7) for the financial support.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Rafaela Scalco Ferreira
    • 1
  • Neife Aparecida Guinaim dos Santos
    • 1
  • Nádia Maria Martins
    • 1
  • Laís Silva Fernandes
    • 1
  • Antonio Cardozo dos Santos
    • 1
  1. 1.Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil

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