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Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity by Activating the AMPK/SIRT1, MAPK/Erk, and PI3k/Akt Signaling Pathways.
Neurotox Res. 2019 Jul; 36(1):175-192.NR

Abstract

Peripheral sensory neuropathy (PSN) is a well-known side effect of cisplatin characterized by axonal damage. In the early stage of neurotoxicity, cisplatin affects proteins that modulate neurite outgrowth and neuroplasticity, without inducing mitochondrial damage or apoptosis. There are no preventive therapies for cisplatin-induced peripheral neuropathy; therefore, measures to improve axonal growth and connectivity would be beneficial. Caffeic acid phenethyl ester (CAPE) is a bioactive component of propolis with neurotrophic and neuroprotective activities. We have recently showed that CAPE protects against cisplatin-induced neurotoxicity by activating NGF high-affinity receptors (trkA) and inducing neuroplasticity. We have now assessed other potential early targets of cisplatin and additional mechanisms involved in the neuroprotection of CAPE. Cisplatin reduced axonal cytoskeletal proteins (F-actin and β-III-tubulin) without inducing oxidative damage in PC12 cells. It also reduced energy-related proteins (AMPK α, p-AMPK α, and SIRT1) and glucose uptake. At this stage of neurotoxicity, glutamate excitotoxicity is not involved in the toxicity of cisplatin. CAPE attenuated the downregulation of the cytoskeleton and energy-related markers as well as SIRT1 and phosphorylated AMPK α. Moreover, the neuroprotective mechanism of CAPE also involves the activation of the neurotrophic signaling pathways MAPK/Erk and PI3k/Akt. The PI3K/Akt pathway is involved in the upregulation of SIRT1 induced by CAPE, but not in the upregulation of cytoskeletal proteins. Altogether, these findings suggest that the neuroprotective effect of CAPE against cisplatin-induced neurotoxicity involves both (a) a neurotrophic mechanism that mimics the mechanism triggered by the NGF itself and (b) a non-neurotrophic mechanism that upregulates the cytoskeletal proteins.

Authors+Show Affiliations

Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. acsantos@fcfrp.usp.br.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31016689

Citation

Ferreira, Rafaela Scalco, et al. "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, vol. 36, no. 1, 2019, pp. 175-192.
Ferreira RS, Dos Santos NAG, Bernardes CP, et al. Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity by Activating the AMPK/SIRT1, MAPK/Erk, and PI3k/Akt Signaling Pathways. Neurotox Res. 2019;36(1):175-192.
Ferreira, R. S., Dos Santos, N. A. G., Bernardes, C. P., Sisti, F. M., Amaral, L., Fontana, A. C. K., & Dos Santos, A. C. (2019). 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, 36(1), 175-192. https://doi.org/10.1007/s12640-019-00042-w
Ferreira RS, et al. Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity By Activating the AMPK/SIRT1, MAPK/Erk, and PI3k/Akt Signaling Pathways. Neurotox Res. 2019;36(1):175-192. PubMed PMID: 31016689.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity by Activating the AMPK/SIRT1, MAPK/Erk, and PI3k/Akt Signaling Pathways. AU - Ferreira,Rafaela Scalco, AU - Dos Santos,Neife Aparecida Guinaim, AU - Bernardes,Carolina P, AU - Sisti,Flávia Malvestio, AU - Amaral,Lilian, AU - Fontana,Andreia C K, AU - Dos Santos,Antonio Cardozo, Y1 - 2019/04/23/ PY - 2018/10/02/received PY - 2019/04/04/accepted PY - 2019/03/26/revised PY - 2019/4/25/pubmed PY - 2020/1/10/medline PY - 2019/4/25/entrez KW - Axonal regeneration KW - CAPE KW - Cisplatin KW - Neuroprotection KW - Neurotoxicity KW - Neurotrophic signaling KW - Peripheral neuropathy SP - 175 EP - 192 JF - Neurotoxicity research JO - Neurotox Res VL - 36 IS - 1 N2 - Peripheral sensory neuropathy (PSN) is a well-known side effect of cisplatin characterized by axonal damage. In the early stage of neurotoxicity, cisplatin affects proteins that modulate neurite outgrowth and neuroplasticity, without inducing mitochondrial damage or apoptosis. There are no preventive therapies for cisplatin-induced peripheral neuropathy; therefore, measures to improve axonal growth and connectivity would be beneficial. Caffeic acid phenethyl ester (CAPE) is a bioactive component of propolis with neurotrophic and neuroprotective activities. We have recently showed that CAPE protects against cisplatin-induced neurotoxicity by activating NGF high-affinity receptors (trkA) and inducing neuroplasticity. We have now assessed other potential early targets of cisplatin and additional mechanisms involved in the neuroprotection of CAPE. Cisplatin reduced axonal cytoskeletal proteins (F-actin and β-III-tubulin) without inducing oxidative damage in PC12 cells. It also reduced energy-related proteins (AMPK α, p-AMPK α, and SIRT1) and glucose uptake. At this stage of neurotoxicity, glutamate excitotoxicity is not involved in the toxicity of cisplatin. CAPE attenuated the downregulation of the cytoskeleton and energy-related markers as well as SIRT1 and phosphorylated AMPK α. Moreover, the neuroprotective mechanism of CAPE also involves the activation of the neurotrophic signaling pathways MAPK/Erk and PI3k/Akt. The PI3K/Akt pathway is involved in the upregulation of SIRT1 induced by CAPE, but not in the upregulation of cytoskeletal proteins. Altogether, these findings suggest that the neuroprotective effect of CAPE against cisplatin-induced neurotoxicity involves both (a) a neurotrophic mechanism that mimics the mechanism triggered by the NGF itself and (b) a non-neurotrophic mechanism that upregulates the cytoskeletal proteins. SN - 1476-3524 UR - https://www.unboundmedicine.com/medline/citation/31016689/Caffeic_Acid_Phenethyl_Ester__CAPE__Protects_PC12_Cells_Against_Cisplatin_Induced_Neurotoxicity_by_Activating_the_AMPK/SIRT1_MAPK/Erk_and_PI3k/Akt_Signaling_Pathways_ L2 - https://dx.doi.org/10.1007/s12640-019-00042-w DB - PRIME DP - Unbound Medicine ER -