Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity by Activating the AMPK/SIRT1, MAPK/Erk, and PI3k/Akt Signaling Pathways

Autor(es)

Ferreira, Rafaela Scalco ^[1] ; Guinaim dos Santos, Neife Aparecida ^[1] ; Bernardes, Carolina P. ^[1] ; Sisti, Flavia Malvestio ^[1] ; Amaral, Lilian ^[1] ; Fontana, Andreia C. K. ^[2] ; dos Santos, Antonio Cardozo ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, Ribeirao Preto, SP - Brazil

^[2] Drexel Univ, Coll Med, Dept Physiol & Pharmacol, Philadelphia, PA 19104 - USA

• Tipo de documento: Artigo Científico
• Fonte: NEUROTOXICITY RESEARCH; v. 36, n. 1, p. 175-192, JUL 2019.
• Citações Web of Science: 2

Resumo

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 -III-tubulin) without inducing oxidative damage in PC12 cells. It also reduced energy-related proteins (AMPK , p-AMPK , 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 . 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. (AU)

• Processo FAPESP: 17/09332-7 - Neuropatia sensorial periférica induzida pela cisplatina: Estudo dos mecanismos de neurotoxicidade da cisplatina e de neuroproteção do éster fenetil do ácido cafeico (CAPE) em células PC-12
• Beneficiário: Antonio Cardozo dos Santos
• Modalidade de apoio: Auxílio à Pesquisa - Regular