Tanshinone I Induces Mitochondrial Protection through an Nrf2-Dependent Mechanism in Paraquat-TreatedHuman Neuroblastoma SH-SY5Y Cells

Abstract

Tanshinone I (T-I; 1,6-Dimethylnaphtho[1,2-g][1]benzofuran-10,11-dione; C18H12O3), which may be found in Salvia miltiorrhiza Bunge (Danshen), is a potent anti-inflammatory, antioxidant, and anti-cancer agent. At least in part, T-I exerts antioxidant activity by activating signaling pathways associated with the maintenance of the redox state in mammalian cells. In this context, the upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has received attention regarding the role of this transcription factor in modulating the expression of antioxidant enzymes and the metabolism of glutathione (GSH). Even though there is a growing body of evidence suggesting that T-I mediates protection against several pro-oxidant challenges in both in vitro and in vivo experimental models, it remains to be examined whether and how T-I would modulate mitochondrial function during redox disturbances. Therefore, we aimed to reveal whether T-I would exhibit protective effects on mitochondria of SH-SY5Y cells treated with paraquat (PQ), a well-known mitochondrial toxic agent. We found that T-I pretreatment significantly protected mitochondria against PQ-induced redox impairment through an Nrf2-dependent mechanism involving upregulation of antioxidant enzymes, such as Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), and both catalytic and modifier subunits of γ-glutamate-cysteine ligase (γ-GCL). T-I prevented complex I and mitochondrial membrane potential (MMP) impairments elicited by PQ. Thus, T-I may be viewed as a new mitochondrial protective agent whose complete mechanism of action needs to be investigated, but it seems to involve mitochondriotropic aspects related to the chemistry of this molecule.