Accumulating evidence has confirmed the health benefits of walnut diets in maintaining brain function with age. Recent studies have indicated that walnut
polyphenols (WP) and their active metabolites urolithins may play an important role in the health benefits of walnut diets. In the present study, we evaluated the protective effect of WP and
urolithin A (UroA) on H2O2-induced damage in human
neuroblastoma (SH-SY5Y) cells, and investigated its mechanisms in the
cAMP-response element binding protein (CREB)-mediated signaling pathway, which is tightly involved in neurodegenerative and neurological diseases. The results demonstrated that both WP (50 and 100 μg mL-1) and UroA (5 and 10 μM) treatment significantly reversed the decrease of cell viability, the leakage of extracellular
lactate dehydrogenase (LDH), the overload of intracellular
calcium and cell apoptosis induced by H2O2 treatment. Moreover, WP and UroA treatment also relieved H2O2-induced oxidative stress including overproduction of intracellular
reactive oxygen species (ROS) and reduced activities of
superoxide dismutase (SOD) and
catalase (CAT). Additionally, western blot analysis showed that WP and UroA treatment significantly increased the activity of
cAMP-dependent protein kinase A (PKA) and the expression of pCREB (Ser133) and its downstream molecule
brain-derived neurotrophic factor (
BDNF), which were decreased by H2O2 treatment. Furthermore, pretreatment with the
PKA inhibitor H89 abolished the protective effects of WP and UroA, indicating that up-regulation of the PKA/CREB/
BDNF neurotrophic signaling pathway is required for their
neuroprotective effects against oxidative stress. The current work provides new perspectives for understanding the beneficial effects of WP and UroA on brain function, which warrants further investigation.