Pinocembrin (PB; 5,7-dihydroxyflavanone) is found in
propolis and exhibits
antioxidant activity in several experimental models. The
antioxidant capacity of PB is associated with the activation of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. The Nrf2/ARE axis mediates the expression of
antioxidant and detoxifying
enzymes, such as
glutathione peroxidase (GPx),
glutathione reductase (GR),
heme oxygenase-1 (HO-1), and the catalytic (GCLC) and regulatory (GCLM) subunits of the rate-limiting
enzyme in the synthesis of
glutathione (GSH), γ-
glutamate-cysteine ligase (γ-GCL). Nonetheless, it is not clear how PB exerts mitochondrial protection in mammalian cells. Human
neuroblastoma SH-SY5Y cells were pretreated (4 h) with PB (0-25 µM) and then exposed to
methylglyoxal (MG; 500 µM) for further 24 h. Mitochondria were isolated by differential centrifugation. PB (25 µM) provided mitochondrial protection (decreased lipid peroxidation, protein carbonylation, and
protein nitration in mitochondrial membranes; decreased mitochondrial
free radical production; enhanced the content of GSH in mitochondria; rescued mitochondrial membrane potential-
MMP) and blocked MG-triggered cell death by a mechanism dependent on the activation of the extracellular-related
kinase (Erk1/2) and consequent upregulation of Nrf2. PB increased the levels of GPx, GR, HO-1, and mitochondrial GSH. The PB-induced effects were suppressed by silencing of Nrf2 with
siRNA. Therefore, PB activated the Erk1/2-Nrf2 signaling pathway resulting in mitochondrial protection in SH-SY5Y cells exposed to MG. Our work shows that PB is a strong candidate to figure among mitochondria-focusing agents with pharmacological potential.