Abstract
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.
Highlights
During the cerebral ischemia, a rise in intracellular calcium ([Ca2+]i) is thought to initiate a cascade of events leading to the cell death, including activation of proteases and endonucleases, generation of free radicals that destroy cell membranes by lipid peroxidation, and induction of apoptosis [1,2,3,4,5,6]. a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are initially thought to be relatively impermeable to Ca2+, it is clear that there is AMPA receptor (AMPAR) exhibiting considerable Ca2+ permeability
We reported an important role of stimulation and maintenance the activity of PI3K during the early stage (24 h) of propofol post-conditioning, which could improve Morris Water Maze (MWM) performance, increase neurogenesis in the ipsilateral Dentate Gyrus (DG) of hippocampus and inhibit the internalization of AMPAR GluR2 subunit (Ca2+ impermeable AMPARs) up to 28 days for cerebral ischemia/reperfusion injury rats
About 80% of the initially proliferated cells disappear within 4 wk post ischemia, only the long-term surviving neurons may contribute to postischemia recovery [32]
Summary
A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are initially thought to be relatively impermeable to Ca2+, it is clear that there is AMPA receptor (AMPAR) exhibiting considerable Ca2+ permeability. AMPAR-mediated excitotoxicity is thought to play a critical role in CNS ischemic insults [10,11]. We have showed that propofol post-conditioning inhibited AMPAR GluR2 subunit internalization in hippocampal neurons and provided neuroprotection to cerebral ischemia/ reperfusion (I/R) injury. These effects were sustained to 28 days post-ischemia [12]. The maintenance of the surface expression of Ca2+-impermeable AMPARs may play the key protective role during cerebral ischemia/reperfusion injury
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