Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells

Abstract

Neurotrophins such as NGF promote neuronal survival and differentiation via the cell surface TrkA neurotrophin receptor. Compounds with neurotrophic actions that are low in molecular weight and can permeate the blood-brain barrier are promising therapeutic agents against neurodegenerative diseases such as Alzheimer's disease. Carnosic acid (CA), an electrophilic compound in rosemary, activates antioxidant responsive element (ARE)-mediated transcription via activation of Nrf2. In the present study, we discovered that CA strongly promotes neurite outgrowth of PC12h cells. NGF as well as CA activated Nrf2, whereas CA and NGF-mediated neuronal differentiation was suppressed by Nrf2 knockdown. On the other hand, CA activated TrkA-downstream kinase Erk1/2 independently of Nrf2. CA-induced p62/ZIP expression in an Nrf2-dependent manner, while the CA-induced neural differentiation was suppressed by p62/ZIP knockdown. Furthermore, CA-induced ARE activation was attenuated both by p62/ZIP knockdown and a Trk signal inhibitor. These results suggest that the CA induction of p62/ZIP by Nrf2 enhances TrkA signaling which subsequently potentiates Nrf2 pathway. This is the first demonstration that activation of the Nrf2-p62/ZIP pathway by a low-molecular natural electrophilic compound plays important roles in TrkA-mediated neural differentiation and may represent the common molecular mechanism for neurotrophic activities of electrophilic compounds.

Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation

“…Keap1 is a repressor of Nrf2 and functions as an adaptor in the ubiquitination of Nrf2 in Cul3-dependent systems. The Keap1-Nrf2 pathway is regulated by conformational changes in Keap1-Nrf2 interaction in response to oxidative stress [9][10][11]. Consistent with this notion, M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 10 we found that fenofibrate activates the transcription of Nrf2 target genes associated with the down-regulation of Keap1.…”

“…Keap1 acts as a substrate for the ubiquitination of Nrf2, dependent of the Cul3-dependent E3 ubiquitination system. Therefore, Keap1 targets Nrf2 for proteasomal degradation under normal conditions [10,11]. Upon oxidative stress, certain cysteine residues of Keap1 are modified; this induces a conformational change in Keap1 and inhibits proteasomal degradation of Nrf2.…”

“…Upon oxidative stress, certain cysteine residues of Keap1 are modified; this induces a conformational change in Keap1 and inhibits proteasomal degradation of Nrf2. The stabilized Nrf2 is then translocated from the cytosol to the nucleus, where it stimulates the activation of its target genes, including NAD(P)H: quinone oxidoreductase (NQO-1), heme oxygenase-1 (HO-1), and glutathione S-transferase A1 (GSTA1) [10,11].…”

p62/SQSTM1 Is a Target Gene for Transcription Factor NRF2 and Creates a Positive Feedback Loop by Inducing Antioxidant Response Element-driven Gene Transcription

“…Expression of the p62 gene is induced by NRF2 upon exposure to electrophiles, reactive oxygen species, and nitric oxide (38,43,49). Furthermore, p62 protein has been reported to stimulate expression of genes containing an ARE in their promoter regions (39).…”

Antioxidant Activity of Oral Administration of Rosmarinus Officinalis Leaves Extract on Rat's Hippocampus which Exposed to 6-Hydroxydopamine

“…Therefore, dietary supplementation with antioxidants could conceivably protect against the molecular effects of lipid peroxidation, free radicals and ROS and delay the progress of many chronic diseases. Results of the relevant studies showed that there are biologically active compounds in rosemary essential oil exhibiting neuroprotective, antioxidant, anti-carcinogenic and cognition-enhancing properties (Kosaka et al 2010;Zhang et al 2010). It is suggested that the neuroprotective effect of RE occurs partly because of decreased oxidative damage.…”