Role of PI3K/Akt in diazoxide preconditioning against rat hippocampal neuronal death in pilocarpine-induced seizures.
Diazoxide (DZ), a highly selective opener of the mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, has neuroprotective effects. However, the mechanism of DZ protecting hippocampal neurons against cell death in pilocarpine-induced seizures is unknown. In this study, we investigated DZ attenuating neuronal loss caused by pilocarpine-induced seizures in rat hippocampus. DZ inhibited seizure-induced change in phospho-Akt expression, translocation of apoptosis-inducing factor (AIF), release of cytochrome c (CytC) and caspase-3 activation, which could be abolished by preincubation with 5-hydroxydecanoic acid, an inhibitor of mitoK(ATP). In addition, wortmannin, an inhibitor of phosphatidylinositol-3-kinase (PI3K), attenuated the translocation of AIF, CytC release and caspase-3 activation after seizures. DZ could reduce neuronal death induced by seizures in hippocampus by suppressing the translocation of AIF, CytC release and the activation of caspase-3 via the PI3K/Akt pathway.
Department of Neurology, Qilu Hospital, Shandong University, 44#, Wenhua Xi Road, Jinan 250012, China.
Yuan
Y
Xue
Nanchang
N
Xie
Youting
Y
Lin
Jingjing
J
Xu
Yuxiang
Y
Han
Shengjun
S
Wang
Hong
H
Jiang
Zhaofu
Z
Chi
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D003292:Convulsants / Q000633:toxicity; D003981:Diazoxide / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010862:Pilocarpine / Q000633:toxicity; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D003292:Convulsants; D018696:Neuroprotective Agents; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D010862:Pilocarpine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D003981:Diazoxide