Tanshinone I Induces Mitochondrial Protection by a Mechanism Involving the Nrf2/GSH Axis in the Human Neuroblastoma SH-SY5Y Cells Exposed to Methylglyoxal.

Abstract

Methylglyoxal (MG) is a dicarbonyl molecule exhibiting high reactivity and is a major responsible for glycation in human cells. Accumulation of MG is seen in certain diseases, including metabolic disturbances and neurodegeneration. Among other effects, MG promotes mitochondrial dysfunction, leading to bioenergetic decline and redox impairment in virtually any nucleated human cells. The detoxification of MG is dependent on the availability of reduced glutathione (GSH), a major antioxidant that is also utilized in phase II detoxification reactions. The synthesis of GSH is mainly controlled by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The activation of Nrf2 is stimulated by several reactive compounds, including natural molecules produced by plants. Tanshinone I (T-I) is obtained from Salvia miltiorrhiza Bunge and exerts potent cytoprotective actions in different cell types. Thus, we have investigated here whether and how T-I would be able to protect mitochondria of the human neuroblastoma SH-SY5Y cell line exposed to MG. The cells were pretreated with T-I at 2.5μM for 2h before the challenge with MG at 500μM. T-I significantly attenuated the MG-induced loss of cell viability, bioenergetic decline, and redox impairment in SH-SY5Y cells. The inhibition of the GSH synthesis by buthionine sulfoximine (BSO) at 100μM suppressed the mitochondrial protection promoted by T-I. The silencing of Nrf2 by small interfering RNA (siRNA) abrogated the synthesis of GSH and the mitochondrial protection stimulated by T-I in SH-SY5Y cells. Therefore, T-I induced mitochondrial protection by a mechanism involving the Nrf2/GSH axis in MG-challenged SH-SY5Y cells.