Ebselen attenuates oxidative stress‐induced apoptosis via the inhibition of the c‐Jun N‐terminal kinase and activator protein‐1 signalling pathway in PC12 cells

Abstract

1 Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one) is a selenoorganic compound exhibiting both glutathione peroxidase activity and antioxidant activity. Although it has been reported that ebselen is e ective for oxidative stress-induced neuronal damage both in vivo and clinically, the precise mechanisms of the e cacy have not yet been elucidated. Thus, we hypothesized that ebselen may a ect reactive oxygen species-induced mitogen-activated protein (MAP) kinase activation in cultured PC12 cells. 2 Our ®ndings showed that hydrogen peroxide (H 2 O 2 ) stimulated rapid and signi®cant activation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 in PC12 cells, which is a model of catecholamine-containing neurons. 3 H 2 O 2 -induced JNK activation was inhibited by ebselen, whereas ERK1/2 and p38 activation by H 2 O 2 were not a ected by ebselen. 4 Inhibition by ebselen of H 2 O 2 -induced hydroxyl radical generation in PC12 cells was observed using electron paramagnetic resonance measurements. Ebselen also inhibited H 2 O 2 -induced increases in DNA binding activity of activator protein-1 (AP-1), a downstream transcription factor of JNK, composed of the c-Jun homo/heterodimer. 5 Finally, pretreatment of cells with ebselen resulted in a signi®cant recovery from cell death including apoptosis by H 2 O 2 in PC12 cells. 6 These ®ndings suggest that ebselen attenuates oxidative stress-induced neuronal cell death through the inhibition of the JNK and AP-1 signalling pathway. Thus, inhibition of JNK by ebselen may imply its usefulness for treatment of ischaemic cerebral diseases relevant to neuronal cell death.

Cytosolic Peroxiredoxin Attenuates The Activation Of Jnk And P38 But Potentiates That Of Erk In Hela Cells Stimulated With Tumor Necrosis Factor-α

“…Exogenous H 2 O 2 has been shown to activate all three types of MAPK in many cell types, including HeLa cells (4,18,(45)(46)(47)(48)(49)(50). We have also confirmed the activation of all three types of MAPK in HeLa cells by exogenous H 2 O 2 (data not shown).…”

Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats

“…Conversely, the 30 mg/kg dose of ebselen significantly increased the apoptotic index. Our results were consistent with previous studies [30,[33][34][35][36]. Yang et al demonstrated that ebselen led to a dose-dependent increase of TUNEL-positive cells, which depleted intracellular glutathione (GSH) and protein thiols [35].…”

Effect of angiotensin II on iron-transporting protein expression and subsequent intracellular labile iron concentration in human glomerular endothelial cells

“…However, HGECs treated with Ang II and 90% Tf for 6 h showed 1:2:2:1 quartet EPR signals with hyperfine coupling constants of a N ¼a H ¼1.49 mT (Figure 5d), which were consistent with the reported values for the DMPO/ OH spin adduct. 38,42 These findings indicated that Ang II and 90% Tf facilitated OH generation in HGECs.…”

“…38 HGECs were seeded (1Â10 5 cells cm À2 ) and grown to subconfluence in 60-mm culture dishes in CSC growth medium-10% fetal bovine serum. Cells were pretreated with or without 90% Tf (50 mM) for 5 min, then treated with or without Ang II (1 nM) for 6 h at 37 1C, and then cells were washed twice with PBS.…”