Dietary flavonoids, including the citrus flavanone hesperetin, may have stimulatory effects on cytoprotective intracellular signalling pathways. In primary mouse cortical neurone cultures, but not SH-SY5Y human neuroblastoma cells or human primary dermal fibroblasts (Promocells), hesperetin (100-300nM, 15min) caused significant increases in the level of ERK1/2 phosphorylation, but did not increase CREB phosphorylation. Administration of hesperetin for 18h did not alter gene expression driven by the cyclic AMP response element (CRE), assessed using a luciferase reporter system, but 300nM hesperetin partially reversed staurosporine-induced cell death in primary neurones. Our data show that hesperetin is a neuroprotective compound at concentrations where antioxidant effects are unlikely to predominate. The effects of hesperetin are cell-type dependent and, unlike the flavanol (-)epicatechin, neuroprotection in vitro is not associated with enhanced CREB phosphorylation or CRE-mediated gene expression.
Rainey-Smith, S., Schroetke, L-W., Bahia, P., Fahmi, A., Skilton, R., Spencer, J. P. E., Rice-Evans, C., Rattray, M., & Williams, R. J. (2008). Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation. Neuroscience Letters, 438(1), 29-33. https://doi.org/10.1016/j.neulet.2008.04.056