Carnosic Acid Protects Mitochondria of Human Neuroblastoma SH-SY5Y Cells Exposed to Paraquat Through Activation of the Nrf2/HO-1Axis

Carnosic acid (CA; C20H28O4), which is also called salvin, is a major phenolic diterpene found in Rosmarinus officinalis L. and exhibits antioxidant, anti-inflammatory, and antiproliferative properties. CA activates the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, leading to the upregulation of antioxidant and phase II detoxification enzymes, such as heme oxygenase-1 (HO-1), glutathione reductase (GR), gamma-glutamate-cysteine ligase (gamma-GCL), and glutathione S-transferase (GST), among others. We have previously demonstrated that CA upregulates the total and mitochondrial synthesis of glutathione (GSH), causing mitochondrial protection against paraquat (PQ) and methylglyoxal (MG). Nonetheless, the complete mechanism by which CA prevented mitochondrial dysfunction was not clear yet. Here, we examine whether HO-1 would be involved in the CA-induced mechanism of mitochondrial protection in SH-SY5Y-treated cells. SH-SY5Y cells were pretreated with CA (1 mu M) for 12 h prior to a challenge with PQ at 100 mu M for additional 24 h. Zinc protoporphyrin IX (ZnPP IX; a specific inhibitor of HO-1; 10 mu M) was utilized prior to exposure to CA in order to investigate whether HO-1 was involved in the cytoprotective effects elicited by CA. We found that the CA-induced Nrf2-dependent HO-1 upregulation ameliorated, at least in part, the mitochondrial function in PQ-treated cells. Therefore, CA protected mitochondria of SH-SY5Y cells and exerted antiapoptotic effects by activating the Nrf2/HO-1 axis.