Neuroprotection of selenite against ischemic brain injury through negatively regulating early activation of ASK1/JNK cascade via activation of PI3K/AKT pathway
Abstract
Aim: To investigate whether selenite, a known antioxidant, could decrease the
activation of apoptosis signal regulating kinase 1/c-jun N-terminal kinase (ASK1/
JNK) signaling cascade in cerebral ischemia/reperfusion (I/R) by activating the
phosphatidylinositol 3-kinase (PI3K)/AKT pathway in rat hippocampi, and the
neuroprotective effect of selenite against ischemic injury after 15 min of transient
brain ischemia. Methods: Transient global brain ischemia was induced by
4-vessel occlusion into adult male Sprague-Dawley rats weighing 250–300 g. The
rats were pretreated only with selenite (0.3 mg/kg dissolved in 0.9% saline) every
24 h for 7 d by means of intravenous injection of the tail or combined with LY294002
from d 5 by left cerebral ventricle injection before surgery. Results: Selenite
significantly increased AKT1 activation and decreased the activation of ASK1/
JNK cascade via phosphorylating ASK1 at Ser-83 residue by AKT1 during early
reperfusion after 15 min transient global brain ischemia. On the contrary, combined
pretreatment of the rats with LY294002 (a specific PI3K inhibitor) and selenite
significantly inhibited the effects solely with selenite. Conclusion: The activation
of the pro-apoptotic ASK1/JNK cascade, which is closely associated with
oxidative stress, could be suppressed by selenite through activating the antiapoptotic
PI3K/AKT pathway during early reperfusion after cerebral ischemia in
rat hippocampi.
Keywords:
activation of apoptosis signal regulating kinase 1/c-jun N-terminal kinase (ASK1/
JNK) signaling cascade in cerebral ischemia/reperfusion (I/R) by activating the
phosphatidylinositol 3-kinase (PI3K)/AKT pathway in rat hippocampi, and the
neuroprotective effect of selenite against ischemic injury after 15 min of transient
brain ischemia. Methods: Transient global brain ischemia was induced by
4-vessel occlusion into adult male Sprague-Dawley rats weighing 250–300 g. The
rats were pretreated only with selenite (0.3 mg/kg dissolved in 0.9% saline) every
24 h for 7 d by means of intravenous injection of the tail or combined with LY294002
from d 5 by left cerebral ventricle injection before surgery. Results: Selenite
significantly increased AKT1 activation and decreased the activation of ASK1/
JNK cascade via phosphorylating ASK1 at Ser-83 residue by AKT1 during early
reperfusion after 15 min transient global brain ischemia. On the contrary, combined
pretreatment of the rats with LY294002 (a specific PI3K inhibitor) and selenite
significantly inhibited the effects solely with selenite. Conclusion: The activation
of the pro-apoptotic ASK1/JNK cascade, which is closely associated with
oxidative stress, could be suppressed by selenite through activating the antiapoptotic
PI3K/AKT pathway during early reperfusion after cerebral ischemia in
rat hippocampi.