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 24h 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.
Subject(s)
Microglia/drug effects , Morpholines/pharmacology , Neuroprotective Agents/pharmacology , Sirolimus/pharmacology , Subarachnoid Hemorrhage/drug therapy , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Apoptosis/physiology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Brain Edema/drug therapy , Brain Edema/metabolism , Brain Edema/pathology , Capillary Permeability/drug effects , Capillary Permeability/physiology , Cell Polarity/drug effects , Cell Polarity/physiology , Cells, Cultured , Disease Models, Animal , Microglia/metabolism , Necrosis/drug therapy , Necrosis/metabolism , Necrosis/pathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Phosphorylation/drug effects , Random Allocation , Rats, Sprague-Dawley , Subarachnoid Hemorrhage/metabolism , Subarachnoid Hemorrhage/pathology , TOR Serine-Threonine Kinases/metabolismABSTRACT
Objective This systematic review aimed to define the relationship between diabetes mellitus (DM) and the risk of aneurysmal subarachnoid haemorrhage (aSAH). Methods Studies associated with DM and aSAH published until March 2016 were retrieved from Pubmed, Embase, Web of Science, and Cochrane Library databases. A random-effects model was used to calculate the relative risks (RRs) with 95% confidence intervals (CIs). Results Eighteen observational studies were retrieved. The overall RRs for DM and aSAH were RRs = 0.59 (0.44, 0.79), with moderate heterogeneity ( I2 = 55.7%, Pheterogeneity = 0.000). Subgroup analysis by study quality revealed a reduced association between DM and aSAH risk in high quality studies only (RRs = 0.40, 95% CI: 0.29, 0.56; I2 = 0.0%, Pheterogeneity = 0.549), therefore study quality may be a source of heterogeneity. Conclusion A potential decreased risk of aSAH in DM patients was found in high quality studies. Further studies are required to confirm this causal relationship and to investigate the biological mechanisms.
