Calcium sensing receptor contribute to early brain injury through the CaMKII/NLRP3 pathway after subarachnoid hemorrhage in mice.

The subversive role of Calcium sensing receptor (CaSR) in cerebral ischemia and traumatic brain injury has been recently reported. Nevertheless, the role of CaSR in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unexplored. Using the endovascular perforation model in mice, this study was aimed at investigating the role and potential mechanism of CaSR in EBI after SAH. Gadolinium trichloride (GdCI3), an agonist of CaSR, and NPS-2143, an inhibitor of CaSR, were administered intraperitoneally. The CaMKII inhibitor KN-93 was injected to intracerebroventricular. We found that CaSR expression was increased and widely expressed in neurons, astrocytes, and microglia after SAH. GdCI3 further deteriorated neurological function, brain edema, neurodegeneration, which were alleviated by NPS-2143. Also, GdCI3 increased the level of CaMKII phosphorylation, and upregulated expression of NLRP3, cleaved caspase-1, and IL-1ß, which were attenuated by NPS-2143. Besides, CaMKII inhibitor KN-93 down-regulated the upregulated expression of NLRP3, cleaved caspase-1, and IL-1ß induced by GdCI3. In conclusion, CaSR activation promotes early brain injury, which may be related to the CaMKII/NLRP3 signaling pathway.

Conditional survival estimates for ependymomas reveal the dynamic nature of prognostication.

BACKGROUND: Traditional survival analysis is frequently used to assess the prognosis of ependymomas (EPNs); however, it may not provide additional survival insights for patients who have survived for several years. Thus, the conditional survival (CS) pattern of this disease is yet to be further investigated. This study aimed to evaluate the improvement of survival over time using CS analysis and develop a CS-based nomogram model for real-time dynamic survival estimation for EPN patients. METHODS: Data on patients with EPN were collected from the Surveillance, Epidemiology, and End Results (SEER) database. In order to construct and validate the model effectively, the selected patients were randomly divided at 7:3 ratio. CS is defined as the probability of surviving for a specified time period (y years) after initial diagnosis, given that the patient has survived x years. The CS pattern of EPN patients were explored. Then, the least absolute shrinkage and selection operator (LASSO) regression method with tenfold cross-validation was employed to identify prognostic predictors. Multivariate Cox regression was employed to develop a CS-based nomogram model, and we used this model to quantify EPN patient risk. Finally, the performance of the prediction model was also evaluated and verified. RESULTS: In total, 1829 patients diagnosed with EPN were included in the study, with 1280 and 549 patients in the training and validation cohorts, respectively. The CS analysis demonstrated that patients' OS saw gradual improvements over time. With each additional year of survival post-diagnosis, the 10-year survival rate of EPN patients saw an increase, updating from 74% initially to 79%, 82%, 85%, 87%, 89%, 91%, 93%, 96%, and 98% (after surviving for 1-9 years, respectively). The LASSO regression model, which implements tenfold cross-validation, identified 7 significant predictors (age, tumor grade, tumor site, tumor extension, tumor size, surgery and radiotherapy) to develop a CS-based nomogram model. And further risk stratification was conducted based on nomogram model for these patients. Furthermore, this survival prediction model was successfully validated. CONCLUSION: This study described the CS pattern of EPN patients and highlighted the gradual improvement of survival observed over time for long-term survivors. We also developed the first novel CS-nomogram model that enabled individualized and real-time prognosis prediction. But patients must be counselled that individual circumstances may not always accurately reflect the findings of the nomogram.

Neutrophil Extracellular Traps may be a Potential Target for Treating Early Brain Injury in Subarachnoid Hemorrhage.

Neuroinflammation is closely associated with poor prognosis in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the role of neutrophil extracellular traps (NETs), which are important regulators of sterile inflammation, in SAH. In this study, markers of NET formation, quantified by the level of citrullinated histone H3 (CitH3), were significantly increased after SAH and correlated with SAH severity. CitH3 peaked at 12 h in peripheral blood and at 24 h in the brain. Administration of the peptidyl arginine deiminase 4 (PAD4) selective antagonist GSK484 substantially attenuated SAH-induced brain edema and neuronal injury. Moreover, the benefit of NET inhibition was also confirmed by DNAse I treatment and neutrophil depletion. Mechanistically, NETs markedly exacerbated microglial inflammation in vitro. NET formation aggravated neuroinflammation by promoting microglial activation and increased the levels of TNF-α, IL-1ß, and IL-6, while inhibiting NETs demonstrated anti-inflammatory effects by decreasing the levels of these proinflammatory factors. Moreover, neurogenic pulmonary edema (NPE), a severe nonneurological complication after SAH, is associated with a high level of NET formation. However, GSK484 effectively inhibited the formation of NETs in the lungs of NPE mice, thereby preventing the diffusion of neutrophilic infiltration and attenuating the swelling of the alveolar interstitium. In conclusion, NETs promoted neuroinflammation after SAH, while pharmacological inhibition of PAD4-NETs could reduce the inflammatory damage caused by SAH. These results supported the idea that NETs might be potential therapeutic targets for SAH.

Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage.

Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.