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Appropriate autophagy has protective effects on ischemic nerve tissue, while excessive autophagy may cause cell death. The inflammatory response plays an important role in the survival of nerve cells and the recovery of neural tissue after ischemia. Many studies have found an interaction between autophagy and inflammation in the pathogenesis of ischemic stroke. This study outlines recent advances regarding the role of autophagy in the post-stroke inflammatory response as follows. (1) Autophagy inhibits inflammatory responses caused by ischemic stimulation through mTOR, the AMPK pathway, and inhibition of inflammasome activation. (2) Activation of inflammation triggers the formation of autophagosomes, and the upregulation of autophagy levels is marked by a significant increase in the autophagy-forming markers LC3-II and Beclin-1. Lipopolysaccharide stimulates microglia and inhibits ULK1 activity by direct phosphorylation of p38 MAPK, reducing the flux and autophagy level, thereby inducing inflammatory activity. (3) By blocking the activation of autophagy, the activation of inflammasomes can alleviate cerebral ischemic injury. Autophagy can also regulate the phenotypic alternation of microglia through the nuclear factor-κB pathway, which is beneficial to the recovery of neural tissue after ischemia. Studies have shown that some drugs such as resveratrol can exert neuroprotective effects by regulating the autophagy-inflammatory pathway. These studies suggest that the autophagy-inflammatory pathway may provide a new direction for the treatment of ischemic stroke.

Background Cerebral ischemia–reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization and subsequent inflammatory response may be a potential adjunct therapy to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory and pro-resolving properties in models of cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced microglia/macrophage polarization has not yet been fully elucidated. Methods We retrospectively collected blood samples from AIS patients who underwent successful recanalization by EVT and analyzed ANXA1 levels longitudinally before and after EVT and correlation between ANXA1 levels and 3-month clinical outcomes. We also established a C57BL/6J mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro model of oxygen–glucose deprivation and reoxygenation (OGD/R) in BV2 microglia and HT22 neurons to explore the role of Ac2-26, a pharmacophore N-terminal peptide of ANXA1, in regulating the I/R-induced microglia/macrophage activation and polarization. Results The baseline levels of ANXA1 pre-EVT were significantly lower in 23 AIS patients, as compared with those of healthy controls. They were significantly increased to the levels found in controls 2–3 days post-EVT. The increased post-EVT levels of ANXA1 were positively correlated with 3-month clinical outcomes. In the mouse model, we then found that Ac2-26 administered at the start of reperfusion shifted microglia/macrophage polarization toward anti-inflammatory M2-phenotype in ischemic penumbra, thus alleviating blood–brain barrier leakage and neuronal apoptosis and improving outcomes at 3 days post-tMCAO/R. The protection was abrogated when mice received Ac2-26 together with WRW4, which is a specific antagonist of formyl peptide receptor type 2/lipoxin A4 receptor (FPR2/ALX). Furthermore, the interaction between Ac2-26 and FPR2/ALX receptor activated the 5’ adenosine monophosphate-activated protein kinase (AMPK) and inhibited the downstream mammalian target of rapamycin (mTOR). These in vivo findings were validated through in vitro experiments. Conclusions Ac2-26 modulates microglial/macrophage polarization and alleviates subsequent cerebral inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway. It may be investigated as an adjunct strategy for clinical prevention and treatment of cerebral I/R injury after recanalization. Plasma ANXA1 may be a potential biomarker for outcomes of AIS patients receiving EVT.

Abstract BACKGROUND Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is an important determinant of clinical outcomes. However, a major hindrance to studies of EBI is the lack of radiographic surrogate marker. OBJECTIVE To propose a scoring system based on early changes in clinically obtained computed tomography (CT), called the Subarachnoid hemorrhage Early Brain Edema Score (SEBES). METHODS Patients with spontaneous aneurysmal SAH and a CT within 24 h of ictus were included. We defined SEBES as a scale of 0 to 4 points according to the (1) absence of visible sulci caused by effacement of sulci or (2) absence of visible sulci with disruption of the gray–white matter junction at 2 predetermined levels in each hemisphere. Prognostic value of the SEBES grade for the prediction of delayed cerebral ischemia (DCI) and unfavorable outcomes was assessed. A separate cohort of patients was used as a validation cohort. RESULTS Of the 164 subjects in our study, high-grade SEBES (3 or 4 points) was identified in 48 patients (29.3%). CT interobserver reliability of SEBES grades was high with a Kappa value of 0.89. After adjusting for covariables, SEBES was identified as an independent predictor of DCI (OR = 2.24, 95% CI: 1.58–3.17) and unfavorable outcome (OR = 3.45, 95% CI: 1.95–6.07). In our validation cohort, 84 subjects showed similar predictive power of SEBES for a prediction of DCI and unfavorable long-term outcome. CONCLUSION SEBES may be a surrogate marker of EBI and predicts DCI and clinical outcomes after SAH.

Cerebral ischemia-reperfusion (CI/R) injury is caused by blood flow recovery after ischemic stroke. Chlorogenic acid (CGA, 5-O-caffeoylquinic acid) is a major polyphenol component of L. and Mate ( .). Previous studies have shown that CGA has a significant neuroprotective effect and can improve global CI/R injury. However, the underlying molecular mechanism of CGA in CI/R injury has not been fully revealed. In this study, CI/R rat model was constructed. The rats were randomly divided into nine groups with ten in each group: Control, CGA (500 mg·kg-1), CI/R, CI/R + CGA (20 mg·kg-1), CI/R + CGA (100 mg·kg-1), CI/R + CGA (500 mg·kg-1), ML385 (30 mg·kg-1), CI/R + ML385 (30 mg·kg-1), CI/R + CGA + ML385. Cerebral infarction volume was detected by TTC staining. Brain pathological damage was detected by H&E staining. Apoptosis of cortical cells was detected by TUNEL staining. The expression of related proteins was detected by RT-qPCR and Western blotting. Step-down test and Y maze test showed that CGA dose-dependently mitigated CI/R-induced brain damage and enhanced learning and spatial memory. Besides, CGA promoted the expression of BDNF and NGF in a dose-dependent manner and alleviated CI/R-induced nerve injury. Moreover, CGA increased the activity of SOD and the level of GSH, as well as decreased production of ROS and LDH and the accumulation of MDA. Notably, CGA attenuated oxidative stress-induced brain injury and apoptosis and inhibited the expression of apoptosis-related proteins (cleaved caspase 3 and caspase 9). Additionally, CGA reversed CI/R induced inactivation of Nrf2 pathway and promoted Nrf2, NQO-1 and HO-1 expression. Nrf2 pathway inhibitor ML385 destroyed this promotion. All the data indicated that CGA had a neuroprotective effect on the CI/R rats by regulating oxidative stress-related Nrf2 pathway.

Increased microvessel density in the peri-infarct region has been reported and has been correlated with longer survival times in ischemic stroke patients and has improved outcomes in ischemic animal models.This raises the possibility that enhancement of angiogenesis is one of the strategies to facilitate functional recovery after ischemic stroke. Blood vessels and neuronal cells communicate with each other using various mediators and contribute to the pathophysiology of cerebral ischemia as a unit. In this mini-review, we discuss how angiogenesis might couple with axonal outgrowth/neurogenesis and work for functional recovery after cerebral ischemia. Angiogenesis occurs within 4 to 7 days after cerebral ischemia in the border of the ischemic core and periphery. Post-ischemic angiogenesis may contribute to neuronal remodeling in at least two ways and is thought to contribute to functional recovery. First, new blood vessels that are formed after ischemia are thought to have a role in the guidance of sprouting axons by vascular endothelial growth factor and laminin/β1-integrin signaling. Second, blood vessels are thought to enhance neurogenesis in three stages: 1) Blood vessels enhance proliferation of neural stem/progenitor cells by expression of several extracellular signals, 2) microvessels support the migration of neural stem/progenitor cells toward the peri-infarct region by supplying oxygen, nutrients, and soluble factors as well as serving as a scaffold for migration, and 3) oxygenation induced by angiogenesis in the ischemic core is thought to facilitate the differentiation of migrated neural stem/progenitor cells into mature neurons. Thus, the regions of angiogenesis and surrounding tissue may be coupled, representing novel treatment targets.

Introduction Cerebral ischemia‐reperfusion injury (CIRI) is a common and debilitating complication of cerebrovascular diseases such as stroke, characterized by mitochondrial dysfunction and cell apoptosis. Unraveling the molecular mechanisms behind these processes is essential for developing effective CIRI treatments. This study investigates the role of RACK1 (receptor for activated C kinase 1) in CIRI and its impact on mitochondrial autophagy. Methods We utilized high‐throughput transcriptome sequencing and weighted gene co‐expression network analysis (WGCNA) to identify core genes associated with CIRI. In vitro experiments used human neuroblastoma SK‐N‐SH cells subjected to oxygen and glucose deprivation (OGD) to simulate ischemia, followed by reperfusion (OGD/R). RACK1 knockout cells were created using CRISPR/Cas9 technology, and cell viability, apoptosis, and mitochondrial function were assessed. In vivo experiments involved middle cerebral artery occlusion/reperfusion (MCAO/R) surgery in rats, evaluating neurological function and cell apoptosis. Results Our findings revealed that RACK1 expression increases during CIRI and is protective by regulating mitochondrial autophagy through the PINK1/Parkin pathway. In vitro, RACK1 knockout exacerbated cell apoptosis, while overexpression of RACK1 reversed this process, enhancing mitochondrial function. In vivo, RACK1 overexpression reduced cerebral infarct volume and improved neurological deficits. The regulatory role of RACK1 depended on the PINK1/Parkin pathway, with RACK1 knockout inhibiting PINK1 and Parkin expression, while RACK1 overexpression restored them. Conclusion This study demonstrates that RACK1 safeguards against neural damage in CIRI by promoting mitochondrial autophagy through the PINK1/Parkin pathway. These findings offer crucial insights into the regulation of mitochondrial autophagy and cell apoptosis by RACK1, providing a promising foundation for future CIRI treatments. This study reveals the key role of RACK1 in CIRI. The study finds that RACK1 regulates mitochondrial function and autophagy. The study confirms the centrality of the PINK1/Parkin pathway. The study offers new strategies for treating CIRI. The study provides comprehensive in vitro and in vivo evidence.

Abstract BACKGROUND Immune dysregulation has long been implicated in the development of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE To determine the relationship of inflammatory cell biomarkers with DCI. METHODS We evaluated 849 aSAH patients who were enrolled into a prospective observational cohort study and had a white blood cell (WBC) differential obtained within 72 h of bleed onset. RESULTS WBC count > 12.1 × 109/L (odds ratio 4.6; 95% confidence interval [CI]: 1.9–11, P < 0.001) was the strongest Complete Blood Count (CBC) predictor of DCI after controlling for clinical grade (P < .001), thickness of SAH blood on admission computed tomography (P = .002), and clipping aneurysm repair (P < .001). A significant interaction between clinical grade and WBC count (odds ratio 0.8, 95% CI: 0.6–1.0, P = .02) revealed that good-grade patients with elevated WBC counts (49%: 273/558) had increased odds for DCI indistinguishable from poor-grade patients. Multivariable Cox regression also showed that elevated WBC counts in good-grade patients increased the hazard for DCI to that of poor-grade patients (hazard ratio 2.1, 95% CI 1.3–3.2, P < .001). Receiver operating characteristic curve analysis of good-grade patients revealed that WBC count (area under the curve [AUC]: 0.63) is a stronger DCI predictor than the modified Fisher score (AUC: 0.57) and significantly improves multivariable DCI prediction models (Z = 2.0, P = .02, AUC: 0.73; PPV: 34%; NPV: 92%). CONCLUSION Good-grade patients with early elevations in WBC count have a similar risk and hazard for DCI as poor-grade patients. Good-grade patients without elevated WBC may be candidates to be safely downgraded from the intensive care unit, leading to cost savings for both patient families and hospitals.

Background Inflammatory mechanism has been implicated in delayed cerebral ischemia (DCI) and poor functional outcomes after subarachnoid hemorrhage (SAH). Identification of cytokine patterns associated with inflammation in acute SAH will provide insights into underlying biological processes of DCI and poor outcomes that may be amenable to interventions. Methods Serum samples were collected from a prospective cohort of 60 patients with acute non-traumatic SAH at four time periods (< 24 h, 24–48 h, 3–5 days, and 6–8 days after SAH) and concentration levels of 41 cytokines were measured by multiplex immunoassay. Logistic regression analysis was used to identify cytokines associated with DCI and poor functional outcomes. Correlation networks were constructed to identify cytokine clusters. Results Of the 60 patients enrolled in the study, 14 (23.3%) developed DCI and 16 (26.7%) had poor functional outcomes at 3 months. DCI was associated with increased levels of PDGF-ABBB and CCL5 and decreased levels of IP-10 and MIP-1α. Poor functional outcome was associated with increased levels of IL-6 and MCP-1α. Network analysis identified distinct cytokine clusters associated with DCI and functional outcomes. Conclusions Serum cytokine patterns in early SAH are associated with poor functional outcomes and DCI. The significant cytokines primarily modulate the inflammatory response. This supports earlier SAH studies linking inflammation and poor outcomes. In particular, this study identifies novel cytokine patterns over time that may indicate impending DCI.

Background The present study aimed to verify whether long noncoding RNA (lncRNA) MALAT1 is involved in brain tissue damage induced by ischemia-reperfusion injury, and to explore the mechanism by which MALAT1 regulates aquaporin 4 (AQP4). Methods In this study, we established glucose deprivation (OGD)/reoxygenation (RX) astrocyte cell model and middle cerebral artery occlusion (MCAO)/reperfusion mouse model in vitro and in vivo. Then cell counting kit-8 assay, flow cytometry analysis, Triphenyltetrazolium chloride (TTC) staining, and western blotting were used to determine cell viability, cell apoptosis, cerebral infarction volume, and the abundance of AQP4, respectively. Results We found that the level of MALAT1 was significantly upregulated in both the MCAO/reperfusion model and OGD/RX model. Knockdown of MALAT1 increased cell viability and reduced cell apoptosis in MA-C cells, while an AQP4 siRNA combined with a siRNA targeting MALAT1 could not enhance this effect. Further experiments showed that MALAT1 positively regulated AQP4 expression via miR-145. The MALAT1 siRNA did not alleviate the exacerbation of damage after miR-145 inhibitor action. However, an miR-145 inhibitor reversed the protection effects of MALAT1 , indicating that MALAT1 silencing protects against cerebral ischemia-reperfusion injury through miR-145. TTC staining showed that the infracted area of whole brain was significantly attenuated in treated with sh-MALAT1 group in vivo. Conclusion Taken together, our study confirmed that MALAT1 promotes cerebral ischemia-reperfusion injury by affecting AQP4 expression through competitively binding miR-145, indicating that MALAT1 might be a new therapeutic target for treatment cerebral ischemic stroke.

Abstract BACKGROUND The Barrow Neurological Institute (BNI) scale is a novel quantitative scale measuring maximal subarachnoid hemorrhage (SAH) thickness to predict delayed cerebral ischemia (DCI). This scale could replace the Fisher score, which was traditionally used for DCI prediction. OBJECTIVE To validate the BNI scale. METHODS All patient data were obtained from the prospective aneurysmal SAH multicenter registry. In 1321 patients, demographic data, BNI scale, DCI, and modified Rankin Scale (mRS) score up to the 1-yr follow-up (1FU) were available for descriptive and univariate statistics. Outcome was dichotomized in favorable (mRS 0-2) and unfavorable (mRS 3-6). Odds ratios (OR) for DCI of Fisher 3 patients (n = 1115, 84%) compared to a control cohort of Fisher grade 1, 2, and 4 patients (n = 206, 16%) were calculated for each BNI grade separately. RESULTS Overall, 409 patients (31%) developed DCI with a high DCI rate in the Fisher 3 cohort (34%). With regard to the BNI scale, DCI rates went up progressively from 26% (BNI 2) to 38% (BNI 5) and corresponding OR for DCI increased from 1.9 (1.0-3.5, 95% confidence interval) to 3.4 (2.1-5.3), respectively. BNI grade 5 patients had high rates of unfavorable outcome with 75% at discharge and 58% at 1FU. Likelihood for unfavorable outcome was high in BNI grade 5 patients with OR 5.9 (3.9-8.9) at discharge and OR 6.6 (4.1-10.5) at 1FU. CONCLUSION This multicenter external validation analysis confirms that patients with a higher BNI grade show a significantly higher risk for DCI; high BNI grade was a predictor for unfavorable outcome at discharge and 1FU.