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
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.