Comment on, "Gene expression in a canine basilar artery vasospasm model: a genome-wide network-based analysis".

The study by Sasahara et al. (2008) offers a comprehensive exploration of the molecular mechanisms underlying cerebral vasospasm following subarachnoid hemorrhage, utilizing genome-wide microarray technology and network-based analysis in a canine model. Their work identifies significant gene expression changes, particularly in IL-6, IL-8, and CCL2, which are implicated in cell signaling, host-pathogen interactions, and immune responses. Despite the study's methodological rigor, it is limited by a single time-point analysis and the use of non-injected controls, which may not fully account for procedural effects. Future studies should include a time-course analysis and more appropriate controls, as well as isolate specific cell types to enhance the relevance of the findings. Further research could explore therapeutic interventions targeting the identified pathways, particularly those involved in calcium signaling and inflammation, to develop more effective treatments for cerebral vasospasm.

Post-Thrombectomy Subarachnoid Hemorrhage: Incidence, Predictors, Clinical Relevance, and Effect Modulators.

BACKGROUND: Subarachnoid hemorrhage (SAH) following endovascular thrombectomy (EVT) is a poorly understood phenomenon, and whether it is associated with clinical detriment is unclear. METHODS: This was an explorative analysis of a national database of real-world hospitalizations in the United States. Patients who underwent EVT were included. Patients were divided into SAH and non-SAH groups, and hospitalization outcomes were compared using multivariable logistic regression models. Regression models were also used to identify significant predictors for post-EVT SAH, and significant modulators of SAH's association with hospitalization outcomes were also assessed. RESULTS: A total of 99,219 EVT patients were identified; 6174 (6.2%) had SAH. Overall, SAH was independently associated with increased odds of in-hospital mortality (21.5% vs. 10.6%, adjusted OR 2.53 [95%CI 2.23-2.87], p < 0.001) and lower odds of routine discharge to home with self-care (18.2% vs. 28.0%, aOR 0.58 [95%CI 0.52-0.65], p < 0.001). Distal/medium vessel occlusion (DMVO), coagulopathy, angioplasty or stenting, concurrent intraparenchymal hemorrhage (IPH), and female sex were associated with higher odds of SAH. DMVO was associated with particularly heightened risk of death (31.8% vs. 7.9%, aOR 6.99 [95%CI 2.99 to 16.3], p < 0.001), which was an effect size significantly larger than other sites of vascular occlusion (interaction p > 0.05). CONCLUSION: SAH is an uncommon but likely clinically detrimental post-EVT complication. DMVO, coagulopathy, angioplasty or stenting, concurrent IPH, and female sex were independently associated with higher odds of post-EVT SAH. SAH associated with DMVO-EVT may be particularly harmful.

Dl-3-n-Butylphthalide attenuates early brain injury and delayed neurological dysfunction by regulating NLRP3 inflammasome after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe neurological event lacking of effective therapy. Early brain injury (EBI) and delayed neurological dysfunction are important cause in the poor prognosis of patients with SAH. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation has been implicated in many inflammatory lesion pathogeneses including SAH. Dl-3-n-butylphthalide (NBP) has been reported to possess substantial anti-inflammatory properties, which is beneficial for various neurodegenerative diseases. However, the effect and molecular mechanisms of NBP on SAH have not been clearly identified. We designed this study to investigate the effect of NBP against EBI and delayed neurological dysfunction after SAH and to reveal the possible underlying mechanism. The adult mice were subjected to endovascular perforation SAH model or sham operation. Mice were randomized to sham group, SAH group, or SAH+NBP group. The EBI (short-term study) was studied at 48h post-SAH and delayed neurological dysfunction (long-term study) at 21 days post-SAH. The results suggested that NBP evidently alleviated the EBI in mice at 48h post-SAH, as shown by elevating neurological score, reducing brain edema, blood-brain barrier disruption, neuronal loss, and astrocyte aggregation, as well as ameliorating cerebral vasospasm. Moreover, NBP was able to improve long-term neurobehavioral functions and decrease neuronal apoptosis at 21 days after SAH. Significantly, NBP treatment also inhibited the expressions of NLRP3, ASC, caspase-1, cleaved-caspase-1, IL-1ß, IL-18, GSDMD and GSDMD-N in both EBI and delayed neurological dysfunction indued by SAH. Our findings suggested that NBP treatment exerts a profound neuroprotective effect against early brain injury and delayed neurological dysfunction induced by SAH, at least partially through regulating NLRP3 inflammasome signaling pathway and its related inflammation and pyroptosis.

White matter abnormalities in aneurysmal and angiographically negative subarachnoid hemorrhage: A diffusion kurtosis imaging study.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) and angiographically negative subarachnoid hemorrhage (anSAH) cause an abrupt rise in intracranial pressure, resulting in shearing forces, causing damage to the white matter tracts. This study aims to investigate whole-brain white matter abnormalities with diffusion kurtosis imaging (DKI) after both aSAH and anSAH and explores whether these abnormalities are associated with impaired cognitive functioning. METHODS: Five months post-ictus, 34 patients with aSAH, 24 patients with anSAH and 17 healthy controls (HC) underwent DKI MRI scanning and neuropsychological assessment (measuring verbal memory, psychomotor speed, executive control, and social cognition). Differences in DKI measures (fractional anisotropy, mean diffusivity, axial diffusivity [AD], radial diffusivity, and mean kurtosis) were examined using tract-based spatial statistics. Significant voxel masks were then correlated with neuropsychological scores. RESULTS: All DKI measures differed significantly between patients with aSAH and HC, but no significant differences were found between patients with anSAH and HC. Although the two SAH groups did not differ significantly on all DKI parameters, effect sizes indicated that the anSAH group might be more similar to HC. Cognitive impairments were found for both SAH groups relative to HC. No significant associations were found between these impairments and white matter abnormalities in the aSAH group, but lower psychomotor speed scores were associated with higher AD values (r = -0.41, p = 0.04) in patients with anSAH. CONCLUSIONS: Patients with aSAH showed significant white matter diffusion abnormalities, while the anSAH group, despite cognitive deficits, did not. However, there were no significant differences between the SAH groups, and no correlations between DKI metrics and cognitive measures, except for one test on psychomotor speed in the anSAH group. Overall, this study suggests that while anSAH may not be as severe as aSAH, it is still not a benign condition. Further research with larger anSAH cohorts is necessary to gain a more precise understanding of white matter injuries, particularly regarding their prevalence.

Differentiating Myelography Contrast from Intraventricular and Subarachnoid Hemorrhage Using Dual-Energy CT of the Head: A Case Report and a Review of Literature.

Single-energy computed tomography (SECT) head is a common diagnostic tool to evaluate for intracranial hemorrhage in emergency settings due to its widespread accessibility and non-invasive nature. However, SECT has densitometric evaluation limitations. For example, hyperdensities on SECT such as blood product and iodine contrast appear similarly. Dual-energy CT (DECT) is a relatively under-utilized imaging modality that has the capability to differentiate between multiple materials. This imaging technique can be extremely useful in identifying materials that are otherwise indistinguishable from standard SECT. The authors present a case of a patient with findings suspicious of intraventricular and subarachnoid hemorrhage on conventional SECT. The suspected hemorrhage was subsequently ruled out utilizing DECT, as iodinated contrast can be subtracted out, yielding an image that can differentiate iodine contrast from blood or other hyperdense material. The authors discuss the underlying physics, potential advantages, and limitations of the DECT.

Comment on, "Differential DNA methylation associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a systematic review".

The article "Differential DNA Methylation Associated with Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: A Systematic Review" by Tomasz Klepinowski et al. offers an in-depth analysis of the relationship between DNA methylation and delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). By systematically reviewing databases like PubMed, MEDLINE, Scopus, and Web of Science, the authors identify key genes, including ITPR3, HAMP, INSR, and CDHR5, as potential biomarkers for early DCI diagnosis. Their meticulous adherence to PRISMA guidelines and the STROBE statement for quality assessment enhances the study's credibility. However, the review could be improved by discussing methodological variability, statistical power, and the functional relevance of identified CpG sites. Additional sections on mechanistic pathways, integration with other omics data, clinical translation, and ethical considerations would further strengthen the review, providing a more comprehensive understanding of epigenetic factors in DCI and paving the way for future therapeutic interventions.

Prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage in the USA.

BACKGROUND AND PURPOSE: Cerebral infarction remains an important cause of death or disability in patients with aneurysmal subarachnoid hemorrhage (SAH). The prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal SAH at a national level are not known. METHODS: We identified the proportion of patients who develop cerebral infarction (ascertained using validated methodology) among patients with aneurysmal SAH and annual trends using the Nationwide Inpatient Sample (NIS) from 2016 to 2021. We analyzed the effect of cerebral infarction on in-hospital mortality, routine discharge without palliative care (based on discharge disposition), poor outcome defined by the NIS SAH outcome measure, and length and costs of hospitalization after adjusting for potential confounders. RESULTS: A total of 35,305 (53.6%) patients developed cerebral infarction among 65,840 patients with aneurysmal SAH over a 6-year period. There was a trend toward an increase in the proportion of patients who developed cerebral infarction from 51.5% in 2016 to 56.1% in 2021 (p trend p<.001). Routine discharge was significantly lower (30.5% vs. 37.8%, odds ratio [OR] 0.82, 95% confidence interval [CI] 0.75-0.89, p<.001), and poor outcome defined by NIS-SAH outcome measure was significantly higher among patients with cerebral infarction compared with those without cerebral infarction (67.4% vs. 59.3%, OR 1.29, 95% CI 1.18-1.40, p<.001). There was no difference in in-hospital mortality (13.0% vs. 13.6%, OR 0.94, 95% CI 0.85-1.05, p = .30). The length of stay (median 18 days [interquartile range [IQR] 13-25] vs. 14 days [IQR 9-20]), coefficient 3.04, 95% CI 2.44-3.52 and hospitalization cost (median $96,823 vs. $71,311, coefficient 22,320, 95% CI 20,053-24,587) were significantly higher among patients who developed cerebral infarction compared with those who did not develop cerebral infarction. CONCLUSIONS: Cerebral infarction was seen in 54% of the patients with a trend toward an increase in the affected proportion of patients with aneurysmal SAH. Patients with cerebral infarction had higher rates of adverse outcomes and required higher resources during hospitalization.

Innovative prognostication: a novel nomogram for post-interventional aneurysmal subarachnoid hemorrhage patients.

Background and purpose: Spontaneous aneurysmal subarachnoid hemorrhage (aSAH) is a common acute cerebrovascular disease characterized by severe illness, high mortality, and potential cognitive and motor impairments. We carried out a retrospective study at Fujian Provincial Hospital to establish and validate a model for forecasting functional outcomes at 6 months in aSAH patients who underwent interventional embolization. Methods: 386 aSAH patients who underwent interventional embolization between May 2012 and April 2022 were included in the study. We established a logistic regression model based on independent risk factors associated with 6-month adverse outcomes (modified Rankin Scale Score ≥ 3, mRS). We evaluated the model's performance based on its discrimination, calibration, clinical applicability, and generalization ability. Finally, the study-derived prediction model was also compared with other aSAH prognostic scales and the model's itself constituent variables to assess their respective predictive efficacy. Results: The predictors considered in our study were age, the World Federation of Neurosurgical Societies (WFNS) grade of IV-V, mFisher score of 3-4, secondary cerebral infarction, and first leukocyte counts on admission. Our model demonstrated excellent discrimination in both the modeling and validation cohorts, with an area under the curve of 0.914 (p < 0.001, 95%CI = 0.873-0.956) and 0.947 (p < 0.001, 95%CI = 0.907-0.987), respectively. Additionally, the model also exhibited good calibration (Hosmer-Lemeshow goodness-of-fit test: X2 = 9.176, p = 0.328). The clinical decision curve analysis and clinical impact curve showed favorable clinical applicability. In comparison to other prediction models and variables, our model displayed superior predictive performance. Conclusion: The new prediction nomogram has the capability to forecast the unfavorable outcomes at 6 months after intervention in patients with aSAH.

Changes in Cerebrospinal Fluid Interleukin-6 Levels after Surgical Treatment of Subarachnoid Hemorrhage.

BACKGROUND: We measured postoperative changes in cerebrospinal fluid (CSF) interleukin (IL)-6 levels in subarachnoid hemorrhage (SAH) due to aneurysm rupture and examined factors associated with outcomes and cerebral vasospasm. We used physiologic saline or artificial CSF as the intraoperative irrigation fluid and examined the differences. METHODS: The participants were 16 men and 41 women who were transported to our facility for SAH and underwent surgical treatment during the period from February 2012 through March 2015. In terms of severity, 31 cases were World Federation of Neurological Surgeons (WFNS) grade I-III and 26 cases were grade IV-V. All cases underwent clipping. Physiologic saline and artificial CSF were used as intraoperative irrigation fluid. We placed a ventricular drainage tube intraoperatively and collected CSF daily from postoperative day (POD) 1 through 10 or until drain removal. RESULTS: IL-6 level varied from 74 pg/mL to 407,936 pg/mL and peaked on PODs 1 and 5. Patients with favorable outcomes had significantly lower postoperative IL-6 levels. POD 1 IL-6 level significantly differed in relation to the presence of cerebral vasospasm but was not associated with its timing or severity. Use of artificial CSF was associated with a significantly lower incidence of cerebral vasospasm. Age and WFNS grade were significantly associated with outcome, and use of artificial CSF had a tendency toward favorable outcomes. CONCLUSIONS: Artificial CSF is a potentially useful intervention when managing subarachnoid hemorrhage.

Treatment factors to suppress delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage based on VASOGRADE: multicenter cohort study.

Delayed cerebral ischemia (DCI) is one of the most important outcome determinants for aneurysmal subarachnoid hemorrhage (aSAH). VASOGRADE, which combines World Federation of Neurological Surgeons grade and modified Fisher grade, is a useful scale for predicting DCI after aSAH. However, no studies have investigated whether VASOGRADE influences the treatment options. We retrospectively analyzed 781 aSAH patients who were prospectively enrolled in 9 primary stroke centers from 2013 to 2021. The total cohort consisted of 76 patients (9.7%) with VASOGRADE-Green, 390 patients (49.9%) with VASOGRADE-Yellow, and 315 patients (40.3%) with VASOGRADE-Red. Worse VASOGRADE had higher incidences of DCI, which occurred in 190 patients (24.3%). As only 5 patients (6.6%) with VASOGRADE-Green developed DCI, we searched for DCI-associated factors in patients with VASOGRADEs-Yellow and -Red. Multivariate analyses revealed independent treatment factors suppressing DCI as follows: no postoperative hemorrhagic complication, combined administration of fasudil hydrochloride and cilostazol, combination of clipping and cisternal drainage, and coiling for VASOGRADE-Yellow; and clipping, and administration of fasudil hydrochloride with or without cilostazol for VASOGRADE-Red. The findings suggest that treatment strategies should be determined based on VASOGRADE to prevent DCI after aSAH.

Follow-up Imaging in Angiography-Negative Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: The aim of this study was to assess the diagnostic yield of follow-up investigations in aneurysm negative SAH patients. MATERIAL AND METHODS: In 109 (25%) of 435 patients with SAH and initial negative DSA, the diagnostic yield of repeat DSA and MRI of the brain and craniocervical junction was reviewed. RESULTS: Of the 109 patients with an initial negative DSA, 51 (47%) had perimesencephalic (PM), 54 (50%) had non-perimesencephalic (NPM) blood distribution, and 4 (3.7%) had CT-negative SAH. A delayed bleeding source was determined in 3 of 82 (3.7%) patients who underwent repeat DSA, and in 1/5 patients who underwent a third DSA. The bleeding patterns of these patients were all NPM (n=4). Repeat DSA did not identify a bleeding source in patients with PM-SAH. MRI of the brain and craniocervical junction after 2 days revealed a bleeding source in 1/105 patients (1%) in a CT-negative SAH. When all diagnostic modalities, including exploratory craniotomy and MRI of the spinal axis were considered, the rate of delayed diagnosis of the bleeding source was 6.4% (7/109). In addition to the bleeding pattern, patients with delayed diagnosis of the bleeding source were characterized by worse disease severity parameters, worse radiological grading scales, and more in-hospital complications than patients without delayed diagnosis of a bleeding source. CONCLUSION: The results of this study support the use of repeat DSA in patients with NPM-SAH, however, routine repeat DSA may not be indicated in PM-SAH patients. The routine use of MRI remains controversial.

Metabolome and transcriptome integration reveals cerebral cortical metabolic profiles in rats with subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe subtype of hemorrhagic stroke. The molecular mechanisms of its secondary brain damage remain obscure. To investigate the alterations in gene and metabolite levels following SAH, we construct the transcriptome and metabolome profiles of the rat cerebral cortex post-SAH using whole transcriptome sequencing and untargeted metabolomics assays. Transcriptomic analysis indicated that there were 982 differentially expressed genes (DEGs) and 540 differentially expressed metabolites (DEMs) between the sham group and SAH 1d, and 292 DEGs and 254 DEMs between SAH 1d and SAH 7d. Most notably, DEGs were predominantly involved in the activation of immune and inflammatory pathways, particularly the Complement and coagulation cascades, TNF signaling pathway, and NOD-like receptor signaling pathway. Metabolic analysis revealed that the metabolic pathways of Arginine and proline, Arachidonic acid, Folate biosynthesis, Pyrimidine, and Cysteine and methionine were remarkably affected after SAH. Metabolites of the above pathways are closely associated not only with immune inflammation but also with oxidative stress, endothelial cell damage, and blood-brain barrier disruption. This study provides new insights into the underlying pathologic mechanisms of secondary brain injury after SAH and further characterization of these aberrant signals could enable their application as potential therapeutic targets for SAH.

Intracranial subarachnoid hemorrhage as part of spinal arteriovenous metameric syndrome.

Spinal Arteriovenous Metameric Syndrome is a rare and complex nonhereditary genetic vascular disorder, affecting multiple layers of tissues at the same metamere, including the spinal cord. We present a case of a 20-year-old man who presented to the emergency department with sudden headache and transient loss of consciousness. Cranial computed tomography scan revealed subarachnoid hemorrhage predominantly in the cerebellar cisterns, fourth ventricle, extending to the basal cisterns. Cerebral angiography showed no abnormalities. Cervical angiographic acquisitions demonstrated a spinal metameric arteriovenous malformation (AVM) at the C3 and C4 levels. Cervical magnetic resonance imaging also confirmed the metameric AVM, revealing both intradural intramedullary and extra-dural vascular lesions in the vertebrae and adjacent soft tissues. The patient was referred for endovascular treatment. Although quite rare, the association between cervical spinal arteriovenous shunt diseases and intracranial hemorrhage has been reported. The bleeding in this case may be attributed to venous reflux into intracranial veins.

Extensive Dural Venous Thrombosis With Associated Intracerebral Hemorrhage and Subarachnoid Hemorrhage Due to Protein S Deficiency: A Case Report.

Cerebral venous thrombosis (CVT) is an uncommon but potentially severe condition, typically affecting younger individuals, pregnant women, and those with underlying thrombophilia. We report a rare case of a 63-year-old female who presented with altered mental status, facial droop, and slurred speech and was found to have an extensive dural venous thrombosis complicated by intracerebral and subarachnoid hemorrhage due to protein S deficiency. Given her diagnosis of protein S deficiency and thrombosis, careful anticoagulation was initiated, resulting in both clinical and radiographic improvement.

Progress of Brain Hypothermia Treatment for Severe Subarachnoid Hemorrhage-177 Cases Experienced and a Narrative Review.

The benefits of hypothermia for the treatment of subarachnoid hemorrhage (SAH) remain controversial. In 1999, we initiated brain hypothermia treatment (BHT) in the hyperacute phase to mitigate the evolution of early brain injury in patients with World Federation of Neurological Surgeons (WFNS) grade V SAH. In June 2014, we introduced endovascular cooling to maintain normothermia for seven days following the initial BHT period. Immediately after the decision to treat the sources of bleeding, cooling was initiated, with a target temperature of 33-34°C. Bleeding sources were extirpated primarily by clipping with decompressive craniectomy. Patients were rewarmed at a rate of ≤1°C/day after ≥48 hours of surface cooling. After being rewarmed to 36°C, temperatures were controlled with antipyretic (chronologically divided into groups A-C with 47, 46, and 46 patients, respectively) or endovascular (group D, 38 patients) cooling. Overall, 177 patients (median age, 62 [52-68] years; 94 [53.1%] women; onset-to-arrival time, 36 minutes [28-50]) were included. The median Glasgow Coma Scale (GCS) score upon admission was 4 (3-6). Median core body temperature was 36 (35.3-36.6)°C on arrival, 34.6 (34.0-35.3)°C on entering the operating room, 33.8 (33.4-34.3)°C upon starting the microsurgical or interventional radiology procedure, and 33.7 (33.3-34.2)°C upon admission to the intensive care unit. There were no significant differences in age, sex, GCS score, pupillary findings, location of bleeding sources, or treatment methods. There were 69 (39.0%) overall favorable outcomes (modified Rankin Scale score of 0-3) at 6 months and 11 (23.4%), 18 (39.1%), 17 (37.0%), and 23 (60.5%) in groups A-D, respectively (p = 0.0065). The outcomes of patients with WFNS grade V SAH improved over time. Herein, we report our experience using BHT for severe SAH through a narrative review.

Temporal Trends and Practice Variation in Early Repair of the Ruptured Aneurysm Among Patients with Aneurysmal Subarachnoid Hemorrhage in the United States, 2012-2019.

BACKGROUND: Early repair of the ruptured cerebral aneurysm (RRCA), preferably within 24 hours of onset, is endorsed by clinical guideline as the preferred management strategy for patients with aneurysmal subarachnoid hemorrhage (aSAH). However, a comprehensive picture of this guideline-recommended usage in contemporary clinical practice is not available. AIMS: This study aimed to characterize trends over time and practice variation in the implementation of an early RRCA strategy among patients with aSAH in a large, national representative data. METHODS: Using data from the 2012-2019 National Inpatient Sample, we measured trends in the proportion of early RRCA, defined as within day 1 of admission, overall, and by demographic and geographical subgroups. Additionally, we created multilevel regression models to quantify hospital-level variation in the early RRCA rates. RESULTS: We identified 82,615 aSAH hospitalizations (mean age, 56.1 years; 68.9% women) undergoing RRCA and, among these, 84.0% (95% CI, 83.4-84.7%) receiving early RRCA. The proportion of early RRCA increased steadily from 82.5% in 2012 to 85.8% in 2019 (P for trend <0.001). The proportion of patients receiving early RRCA across geographic regions ranged from 78.7% to 87.9%, with a median (IQR) of 84.2% (83.0-86.1%). In contrast, the delivery of early RRCA varied widely among hospitals, with a median (IQR) rate of 86.1% (75.0-100.0%) and a range from 0 to 100.0%. The median odds ratio for the early use of RRCA treatment was 1.24 (95% CI, 1.21-1.27) in 2019, indicating 24% increased odds of implementing early RRCA if moving from a lower-use to a higher-use hospital. CONCLUSIONS: Most patients in the United States with aSAH received early RRCA treatment and exhibited an upward trend over the recent 8-year period. However, substantial variation in access to early RRCA was been observed across population subgroups, particularly at the hospital level. Future efforts are necessary to identify further sources of this variation and to develop initiatives that could represent an opportunity to optimize guideline-based quality of care in aSAH management.

12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction and Microthrombi After Subarachnoid Hemorrhage in Mice.

Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus, 12/15-LOX is an important target to prevent delayed cerebral ischemia. SAH was induced in C57BL/6 and 12/15-LOX-/- mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and in vitro. C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day 5 to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. In SAH mice, 12/15-LOX was upregulated in brain vascular cells, and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4-5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH.

Polydatin ameliorates early brain injury after subarachnoid hemorrhage through up-regulating SIRT1 to suppress endoplasmic reticulum stress.

Objective: This study aims to investigate the inhibitory effect of Polydatin (PD) on endoplasmic reticulum (ER) stress following subarachnoid hemorrhage (SAH) and to elucidate the underlying mechanisms. Methods: A standard intravascular puncture model was established to mimic SAH in mice. Neurological functions were assessed using neurological scoring, Grip test, and Morris water maze. Brain edema and Evans blue extravasation were measured to evaluate blood-brain barrier permeability. Western blot and quantitative real-time polymerase chain reaction (PCR) analyses were performed to examine protein and mRNA expressions related to ER stress. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was used to detect cell apoptosis, and transmission electron microscopy was used to observe the ultrastructure of the endoplasmic reticulum. Results: The results indicated that PD significantly reduced brain edema and Evans blue extravasation after SAH, improving neurological function. Compared to the SAH group, the expression levels of ER stress-related proteins including glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were significantly lower in the PD-treated group. Moreover, PD significantly enhances the protein expression of Sirtuin 1 (SIRT1). Validation with sh-SIRT1 confirmed the critical role of SIRT1 in ER stress, with PD's inhibitory effect on ER stress being dependent on SIRT1 expression. Additionally, PD attenuated ER stress-mediated neuronal apoptosis and SAH-induced ferroptosis through upregulation of SIRT1. Conclusion: PD alleviates ER stress following SAH by upregulating SIRT1 expression, thereby mitigating early brain injury. The protective effects of PD are mediated through SIRT1, which inhibits ER stress and reduces neuronal apoptosis and ferroptosis.

Unraveling the protein post-translational modification landscape: Neuroinflammation and neuronal death after stroke.

The impact of stroke on global health is profound, with both high mortality and morbidity rates. This condition can result from cerebral ischemia, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). The pathophysiology of stroke involves secondary damage and irreversible loss of neuronal function. Post-translational modifications (PTMs) have been recognized as crucial regulatory mechanisms in ischemic and hemorrhagic stroke-induced brain injury. These PTMs include phosphorylation, glycosylation, ubiquitination, SUMOylation, acetylation, and succinylation. This comprehensive review delves into recent research on the PTMs landscape associated with neuroinflammation and neuronal death specific to cerebral ischemia, ICH, and SAH. This review aims to explain the role of PTMs in regulating pathologic mechanisms and present critical techniques and proteomic strategies for identifying PTMs. This knowledge helps us comprehend the underlying mechanisms of stroke injury and repair processes, leading to the development of innovative treatment strategies. Importantly, this review underscores the significance of exploring PTMs to understand the pathophysiology of stroke.