Previously, we have shown that the phosphoinositide-3-kinase (PI3K) mediated acute (24 h) post-conditioning neuroprotection induced by
propofol. We also found that
propofol post-conditioning produced long term neuroprotection and inhibited the internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (
AMPA) receptor GluR2 subunit up to 28 days post
middle cerebral artery occlusion (MCAO). However, the relationship between PI3K with
AMPA receptor GluR2 subunit trafficking in
propofol post-conditioning has never been explored. Here we showed that
propofol post-conditioning promoted the binding of PI3K to the C-terminal of
AMPA receptor GluR2 subunit and formed a complex within 1 day after transient MCAO. Interestingly, the enhanced activity of PI3K was observed in the hippocampus of post-conditioning rats at day 1 post
ischemia, whereas the decrease of
AMPA receptor GluR2 subunit internalization was found up to 28 days in the same group. Administration of PI3K selective antagonist
wortmannin inhibited the improvement of spatial learning memory and the increase of neurogenesis in the dentate gyrus up to 28 days post
ischemia. It also reversed the inhibition of
AMPA receptor GluR2 internalization induced by
propofol post-conditioning. Together, our data indicated the critical role of PI3K in regulating the long term neuroprotection induced by
propofol post-conditioning. Moreover, this role was established by first day activation of PI3K and formation of PI3K-AMPA receptor GluR2 complex, thus stabilized the structure of postsnaptic
AMPA receptor and inhibited the internalization of GluR2 subunit during the early stage of
propofol post-conditioning.