＜Symposium III＞Role of Nrf2 in the neurotrophic action of the electrophiles

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Electrophilic compounds, such as curcumin and neurite outgrowth-promoting prostaglandins （NEPPs）,have been known to enhance neurite outgrowth in the presence of small amounts of nerve growth factor （NGF）in PC12 cells. However, the redox-sensitive molecular target for enhanced neurite outgrowth is largely unknown.NGF exerts its function by binding to the cell surface tyrosine kinase receptor, TrkA. Recently, Shibata et al.reported that PTP1B catalyses the dephosphorylation of TrkA. They also demonstrated that an electrophile fromJapanese horseradish Wasabi, 6-methylsulfi nylhexyl isothiocyanate （6-HITC）, inactivates PTP1B causing sustainedphosphorylation and activation of TrkA and promoting neural diff erentiation of PC12 cells. Further, we recentlydiscovered that carnosic acid （CA）, a catechol-type electrophilic compound that is a major ingredient in the herbrosemary, strongly promotes neurite outgrowth of PC12h cells by activating the redox-sensitive transcription factor,Nrf2. Activation of Nrf2 by CA caused a marked induction of p62/ZIP, an important signaling scaff old protein forNGF signaling. Unexpectedly, NGF also activates Nrf2, which is essential for NGF-mediated neural diff erentiation.Thus, electrophiles may enhance neural diff erentiation by both TrkA-dependent and -independent mechanisms.