Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat.

Integrated stress response (ISR) contributes to various neuropathological processes and acting as a therapy target in CNS injuries. However, the fundamental role of ISR in regulating microglial polarization remains largely unknown. Currently no proper pharmacological approaches to reverse microglia-driven neuroinflammation in surgical brain injury (SBI) have been reported. Here we found that inhibition of the crucial ISR effector, activating transcription factor 4 (ATF4), using the RNA interference suppressed the lipopolysaccharide (LPS)-stimulated microglial M1 polarization in vitro. Interestingly, counteracting ISR with a small-molecule ISR inhibitor (ISRIB) resulted in a significant microglial M1 towards M2 phenotype switching after LPS treatment. The potential underlying mechanisms may related to downregulate the intracellular NADPH oxidase 4 (NOX4) expression under the neuroinflammatory microenvironment. Notably, ISRIB ameliorated the infiltration of microglia and improved the neurobehavioral outcomes in the SBI rat model. Overall, our findings suggest that targeting ISR exerts a novel anti-inflammatory effect on microglia via regulating M1/M2 phenotype and may represent a potential therapeutic target to overcome neuroinflammation following SBI.

Factors determining the side of approach for clipping ruptured anterior communicating artery aneurysm via supraorbital eyebrow keyhole approach.

PURPOSE: The purpose of this study was to review the microsurgical anatomy and clipping of ruptured anterior communicating artery (AComA) aneurysms and to plan and avoid complications before operation. METHODS: A total of 523 cases of cerebral aneurysms admitted to the neurosurgery department of the Third Affiliated Hospital of Sun Yat-Sen University from September 2010 to October 2018 were analyzed retrospectively. Among them, 85 patients had ruptured AComA aneurysms. This study was limited to 85 of these cases, whose satisfactory preoperative angiographic diagnostic films can be retrieved from the hospital database system because of the need for detailed review. RESULTS: We performed supraorbital eyebrow keyhole approach (SOEK) craniotomy in 85 patients to clip 85 AComA aneurysms, in the setting of subarachnoid hemorrhage (SAH). Patients' mean age was (52.69 ± 9.94) years (range, 28-78 years). The proportions of small, medium and large aneurysms were 83.5%, 15.3%, and 1.2%, respectively. The average size of the aneurysms was (5.07 ± 2.36) mm. There were 77.8% of patients with inferior aneurysms and 81.3% of patients with superior aneurysms achieved good results. There was a significant correlation between A1 dominance and operation method (p < 0.001). There was no significant relationship between surgical approach and aneurysm projection or A2 plane (p = 0.157 &p = 0.318). CONCLUSION: Regardless of whether the A2 plane is open or closed, the A1 dominant side is still a better choice for accessing AComA aneurysms to avoid dangerous premature bleeding.