Highlights
- •Rapamycin or AZD8055 decreases the activity of mTOR pathway in a rat SAH model.
- •Rapamycin and AZD8055 could attenuate the development of SAH-induced EBI.
- •Rapamycin and AZD8055 inhibit SAH-induced microglia M1 polarization.
- •Rapamycin and AZD8055 promote microglia polarization to a M2 phenotype after SAH.
Abstract
Here, we aimed to study the role and underlying mechanism of mTOR in early brain injury
(EBI) after subarachnoid hemorrhage (SAH). Experiment 1, the time course of mTOR activation
in the cortex following SAH. Experiment 2, the role of mTOR in SAH-induced EBI. Adult
SD rats were divided into four groups: sham group (n = 18), SAH + vehicle group (n = 18), SAH + rapamycin group (n = 18), SAH + AZD8055 group (n = 18). Experiment 3, we incubated enriched microglia with OxyHb. Rapamycin and AZD8055
were also used to demonstrate the mTOR's role on microglial polarization in vitro.
The phosphorylation levels of mTOR and its substrates were significantly increased
and peaked at 24 h after SAH. Rapamycin or AZD8055 markedly decreased the phosphorylation levels of
mTOR and its substrates and the activation of microglia in vivo, and promoted the
microglial polarization from M1 phenotype to M2 phenotype. In addition, administration
of rapamycin and AZD8055 following SAH significantly ameliorated EBI, including neuronal
apoptosis, neuronal necrosis, brain edema and blood-brain barrier permeability. Our
findings suggested that the rapamycin and AZD8055 could attenuate the development
of EBI in this SAH model, possibly through inhibiting the activation of microglia
by mTOR pathway.
Abbreviations:
mTOR (mammalian target of rapamycin), EBI (early brain injury), SAH (subarachnoid hemorrhage), SD (Sprague-Dawley), BBB (blood-brain barrier), aSAH (aneurysmal subarachnoid hemorrhage), ICP (increasing intracranial pressure), CBF (cerebral blood flow), PI3K (phos-phatidylinositol 3-kinase), mTORC1 (mTOR complex 1), RAPA (rapamycin), p70S6K (p70 ribosomal protein S6 kinases), 4EBP1 (4E binding protein 1), TSC (tuberous sclerosis complex), PMSF (phenylmethylsulfonyl fluoride), PVDF (polyvinylidene difluoride), CNS (central nervous system), IPC (ischemic postconditioning)Keywords
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Article info
Publication history
Published online: June 10, 2016
Accepted:
June 9,
2016
Received in revised form:
June 6,
2016
Received:
April 28,
2016
Identification
Copyright
© 2016 Elsevier B.V. All rights reserved.
