Tanshinone I Attenuates the Effects of a Challenge with H 2 O 2 on the Functions of Tricarboxylic Acid Cycle and Respiratory Chain in SH-SY5Y Cells.

Tanshinone I (T-I; C18 H12 O3 ) is a cytoprotective molecule. T-I has been viewed as an antioxidant and anti-inflammatory agent exerting neuroprotective actions in several experimental models. Nonetheless, the mechanisms underlying the beneficial effects of T-I in mammalian cells are not completely understood yet. Mitochondrial dysfunction has been associated with several neurodegenerative diseases which remain uncured. Therefore, there is increasing interest in compounds that may be used in the prevention or treatment of those pathologies. Since T-I presents an antioxidant capacity, we investigated here whether and how this compound would prevent mitochondrial impairment in SH-SY5Y cells exposed to hydrogen peroxide (H2 O2 ), which has been involved in the triggering of deleterious effects in several experimental models mimicking neurodegenerative processes. We found that a pretreatment with T-I at 2.5 μM for 2 h suppressed the pro-oxidant effects of H2 O2 on mitochondrial membranes. Furthermore, T-I prevented the H2 O2 -elicited inhibition of the tricarboxylic acid (TCA) cycle enzymes (aconitase, α-ketoglutarate dehydrogenase, and succinate dehydrogenase) and of the mitochondrial complexes I and V. T-I also abrogated the mitochondrial depolarization and the mitochondrial failure to produce ATP in cells exposed to H2 O2 . T-I upregulated the levels of reduced glutathione (GSH) in the mitochondria of SH-SY5Y cells. T-I induced mitochondrial protection, at least in part, by activating the nuclear factor erythroid 2-related factor 2 (Nrf2), because silencing of Nrf2 by using small interference RNA (SiRNA) blocked these effects. Therefore, T-I afforded mitochondrial protection (involving both redox and bioenergetics-related aspects) against H2 O2 through the activation of Nrf2.