Pro-cellular survival and neuroprotection of citrus flavonoid: the actions of hesperetin in PC12 cells

Hesperetin protects cells against oxidative stress by diverse mechanisms including receptor-mediated actions. PGC-1α and seladin-1 provide potential targets for intervention in oxidative stress-associated neurodegeneration. PC12 cells express TrkA and estrogen receptor (ER). It is known that TrkA triggers the MAPK/ERK1, PI-3 K/Akt, PLCγ/PKC and cAMP/PKA pathways, and membrane ER triggers the MAPK/ERK1, PKA, Akt/PKB or PKC pathway. Using PC12 cells and immunoblotting, we show that hesperetin induces the rapid (15 min) and sustained (∼24 h) expression of PGC-1α (regulated by CREB) and seladin-1 (regulated by ER); hesperetin activates PI-3 K, PKA, PKC, ERK1 and CREB, and it induces PI-3 K, PKA, PGC-1α and seladin-1 via both ER and TrkA; any inhibitor of PI-3 K, PKA or PKC effectively suppresses the activation of ERK1 and CREB as well as the induction of PGC-1α and seladin-1; ERK1 inhibitors effectively suppress hesperetin-induced CREB activation and PGC-1α expression, but have no effect on the induction of seladin-1. This study reveals that hesperetin triggers ER- and TrkA-mediated parallel pathways, collaborating to induce proteins regulated by different transcriptional factors. This novel mechanism explains why hesperetin, although it is known to have relatively low antioxidant and estrogen activities, can exhibit multiple neuroprotective effects.