Neuroprotection of selenite against ischemic brain injury through negatively regulating early activation of ASK1/JNK cascade via activation of PI3K/AKT pathway.
OBJECTIVE
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.


CONCLUSIONS
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.
Wang
Qing
Q
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou 221002, China.
Zhang
Quan-Guang
QG
Wu
Dong-Na
DN
Yin
Xiao-Hui
XH
Zhang
Guang-Yi
GY
D000818:Animals; D029681:Arabidopsis Proteins / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects*; D018038:Sodium Selenite / Q000494:pharmacology*
D029681:Arabidopsis Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D048848:MAP Kinase Kinase Kinase 5; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018038:Sodium Selenite; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494920:Akt1 protein, rat; C519871:MKK4 protein, Arabidopsis