Rosmarinic acid attenuates β-amyloid-induced oxidative stress via Akt/GSK-3β/Fyn-mediated Nrf2 activation in PC12 cells.

Oxidative stress is an important pathogenic factor in Alzheimer's disease (AD). Recently, nuclear factor E2-related factor 2 (Nrf2) has emerged as a master regulator for the endogenous antioxidant response, and thus represents an attractive therapeutic target against AD. The aim of this study is to test the hypothesis that rosmarinic acid (RosA) attenuates amyloid-β (Aβ)-evoked oxidative stress through activating Nrf2-inducible cellular antioxidant defense system. Here, we reported that RosA attenuated Aβ-induced cellular reactive oxygen species (ROS) generation and lipid hydroperoxides (LPO). Interestingly, knockdown of Nrf2 by plasmid-based short hairpin RNA (shRNA) abrogated, at least in part, RosA-mediated neuroprotection in Aβ-challenged PC12 cells. Mechanistically, RosA enhanced the nuclear translocation of Nrf2 and binding to antioxidant response element (ARE) core element but did not induced Nrf2 transcription. Simultaneously, RosA induced a set of Nrf2 downstream target genes encoding phase-II antioxidant enzymes. Furthermore, RosA enhanced protein kinase B (Akt) phosphorylation, glycogen synthase kinase-3β (GSK-3β) phosphorylation at Ser9, and Fyn phosphorylation. Noteworthy, pharmacological inhibition or gene knockdown studies demonstrated that Akt locate upstream of GSK-3β and regulate Nrf2 through Fyn in the context of PC12 cells pre-incubated with RosA following exposed to Aβ. Conversely, the antioxidant effects of RosA could be blocked by Akt inhibitors LY294002, GSK-3β inhibitor LiCl, Nrf2 shRNA, or Fyn shRNA in Aβ-challenged PC12 cells. Consequently, the antioxidant effects of RosA are mediated predominantly by Akt/GSK-3β/Fyn pathway through increased activity of Nrf2. These results suggest, although do not prove, that RosA can be a promising candidate for neuroprotective treatment of AD.

Rong H ，Liang Y ，Niu Y 《-》

Resveratrol Attenuates the Cytotoxicity Induced by Amyloid-β(1-42) in PC12 Cells by Upregulating Heme Oxygenase-1 via the PI3K/Akt/Nrf2 Pathway.

Hui Y ，Chengyong T ，Cheng L ，Haixia H ，Yuanda Z ，Weihua Y ... -  《-》

Astragaloside IV attenuates lead acetate-induced inhibition of neurite outgrowth through activation of Akt-dependent Nrf2 pathway in vitro.

Recently, oxidative stress is strongly associated with lead (Pb)-induced neurotoxicity. We reported previously that Astragaloside IV (AS-IV) possesses potent antioxidant properties. Here, we evaluate the hypothesis that AS-IV attenuates lead acetate (PbAc)-mediated inhibition of neurite outgrowth might mainly result from its antioxidant property via serine/threonine protein kinase (Akt)-dependent activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Interestingly, AS-IV attenuates PbAc-induced inhibition of neurite outgrowth and displayed potential antioxidant properties by inhibiting reactive oxygen species (ROS). Concomitantly, AS-IV enhanced phase II detoxifying enzymes such as heme oxygenase 1 (HO-1), thioredoxin reductase (TrxR), and glutamate cysteine ligase catalytic subunit (GCLc). Conversely, AS-IV had no effect on GCL modulatory subunit (GCLm) and superoxide dismutase (SOD) activity/expression. Furthermore, AS-IV evoked Akt phosphorylation, and subsequent induced phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 (that is, inactivation), which stimulated Nrf2-mediated antioxidant response element (ARE)-containing activation. Importantly, Akt locates upstream of GSK-3β and regulates phase II detoxifying enzymes gene expression through Nrf2 nuclear accumulation in PC12 cells exposed to PbAc. Noteworthy, these results were further confirmed through signalling pathway inhibitors, dominant negative mutant and short hairpin RNA technology. Collectively, these in vitro findings suggest that AS-IV attenuates PbAc-induced inhibition of neurite outgrowth attributed to its antioxidant properties and may be a promising candidate for the treatment of lead developmental neurotoxicity.

Yu C ，Pan S ，Dong M ，Niu Y ... -  《-》

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3β inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3β/Nrf2 pathway.

Zhao Y ，He C ，Hu S ，Ni H ，Tan X ，Zhi Y ，Yi L ，Na R ，Li Y ，Du Q ，Li QX ，Dong Y ... -  《-》

L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice.

Luo L ，Chen J ，Su D ，Chen M ，Luo B ，Pi R ，Wang L ，Shen W ，Wang R ... -  《-》