The Early Stage Formation of PI3K-AMPAR GluR2 Subunit Complex Facilitates the Long Term Neuroprotection Induced by Propofol Post-Conditioning in Rats

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.

Anin vitrostudy of the neuroprotective effect of propofol on hypoxic hippocampal slice

“…Recent studies also have shown that propofol can induce formation of the P13K-AMAR GluR2 sub-unit complex, affect the NF-kB/p53 signalling pathway, inhibit neuron-specific CREB dephosphorylation and reduce the internalization of the AMPAR GluR2 sub-unit [37][38][39][40]. In addition, propofol may reduce the metabolism of neurons, delay the energy exhaustion and maintain the activity of Ca 2+ /Mg 2+ ATPase and Na + /K + ATPase, which is necessary for homeostasis of electrolytes in the cytoplasm.…”

The Role of the PI3K Pathway in the Regeneration of the Damaged Brain by Neural Stem Cells after Cerebral Infarction

“… 60 61 In addition, several chemicals, drugs, and neurotrophic factors have been reported to activate PI3K ( Table 1 ). 62 63 64 65 66 67 68 …”

AMPAergic mechanisms linked to cerebral ischemia

“…The increase of intracellular Ca 2+ causes a cascade of events (proteases/endonucleases activation and production of free radicals that shatter cell membranes) leading to cell death through the induction of apoptosis [84] . On the basis of such observations, it is possible to say that the maintenance of the synaptic exposure of Ca 2+ -impermeable AMPARs may play a protective activity against cerebral ischemia/reperfusion injuries [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85] . This ability resulted to be particularly evident in the brain of hibernating mammals that are able to tolerate severe hypoxia conditions [86] , very probably via the up-regulation of GluR2 that being responsible for low intracellular Ca 2+ levels is consequently responsible for the greater resistance to ischemia-induced neuronal damages .…”

“…Parallel to this capacity, also the persistent neuronal production in some adult brain areas constitutes a potential capacity for self-repairing processes following ischemic cerebral attack [89] . Indeed, after ischemia, neuronal proliferation was up-regulated several fold, and rapidly half of post-ischemic precursors develop neuronal phenotype in some hippocampal fields [85] , that have shown to be the more ischemia-susceptible limbic areas [90] .…”