Prognosis Of Subarachnoid Hemorrhage Research Articles

The pivotal role of microglia in injury and the prognosis of subarachnoid hemorrhage.

Subarachnoid hemorrhage leads to a series of pathological changes, including vascular spasm, cellular apoptosis, blood-brain barrier damage, cerebral edema, and white matter injury. Microglia, which are the key immune cells in the central nervous system, maintain homeostasis in the neural environment, support neurons, mediate apoptosis, participate in immune regulation, and have neuroprotective effects. Increasing evidence has shown that microglia play a pivotal role in the pathogenesis of subarachnoid hemorrhage and affect the process of injury and the prognosis of subarachnoid hemorrhage. Moreover, microglia play certain neuroprotective roles in the recovery phase of subarachnoid hemorrhage. Several approaches aimed at modulating microglia function are believed to attenuate subarachnoid hemorrhage injury. This provides new targets and ideas for the treatment of subarachnoid hemorrhage. However, an in-depth and comprehensive summary of the role of microglia after subarachnoid hemorrhage is still lacking. This review describes the activation of microglia after subarachnoid hemorrhage and their roles in the pathological processes of vasospasm, neuroinflammation, neuronal apoptosis, blood-brain barrier disruption, cerebral edema, and cerebral white matter lesions. It also discusses the neuroprotective roles of microglia during recovery from subarachnoid hemorrhage and therapeutic advances aimed at modulating microglial function after subarachnoid hemorrhage. Currently, microglia in subarachnoid hemorrhage are targeted with TLR inhibitors, nuclear factor-κB and STAT3 pathway inhibitors, glycine/tyrosine kinases, NLRP3 signaling pathway inhibitors, Gasdermin D inhibitors, vincristine receptor α receptor agonists, ferroptosis inhibitors, genetic modification techniques, stem cell therapies, and traditional Chinese medicine. However, most of these are still being evaluated at the laboratory stage. More clinical studies and data on subarachnoid hemorrhage are required to improve the treatment of subarachnoid hemorrhage.

Step-down infusion of barbiturate improves neurofunction in a new rat model of rebleeding subarachnoid hemorrhage

Rebleeding from a ruptured aneurysm is a risk factor for fatal prognosis in subarachnoid hemorrhage (SAH). A novel barbiturate treatment, step-down infusion of barbiturate (sd-B), was previously developed; it showed beneficial effects on patients with severe traumatic brain injuries. The present study established a rebleeding SAH model in rats and evaluated the effect of sd-B. Fifty male Sprague-Dawley rats were divided into sham-operation with distilled water, sham-operation with barbiturate, SAH-rebleeding with distilled water, and SAH-rebleeding with barbiturate groups. For posttreatment with sd-B, thiamylal was intraperitoneally administered at 3 mg/kg/h on days 0–1, 2 mg/kg/h on days 1–2, and 1 mg/kg/h on days 2–3 after SAH using osmotic minipumps. We monitored neurofunction and case fatality as the primary endpoints and evaluated brain injuries, including brain edema and cortical neuronal cell death, as the secondary endpoints. Posttreatment with sd-B improved the modified Garcia test, reduced the brain water content, and inhibited the loss of neuronal cells and microglial expressions in the rat model. Our results revealed that sd-B ameliorated neurofunction and brain injuries on the rebleeding SAH model, suggesting that the novel treatment is a good candidate drug for patients with SAH with rebleeding.

Effect of plasma transfusion on in-hospital mortality and morbidities in patients with spontaneous subarachnoid hemorrhage

ObjectiveSpontaneous subarachnoid hemorrhage (SAH) is a critical condition in which patients may require plasma transfusion during hospitalization. However, it remains unknown whether plasma administration has detrimental effects on the prognosis of SAH beyond the correction of coagulopathy or hypovolemia. This study aimed to analyze the association of plasma transfusion with in-hospital mortality and morbidities in patients with SAH. MethodsWe retrospectively analyzed the data of 1689 adult patients with a primary diagnosis of spontaneous SAH. Differences in the clinical parameters were evaluated between patients who received plasma transfusion and those who did not. ResultsOf 1689 patients, 158 (9.4%) received plasma transfusion. Statistical analysis revealed significant differences in pre-existing comorbidity prevalence between the two study groups. The post-SAH morbidities, including cerebral ischemic events (13.3% vs. 6.4%; p = 0.01), were more common in the plasma transfusion group, whereas the mortality rate was not different between the two study groups (p = 0.166). The mean duration of hospital stay was 19.3 ± 14.4 days and 15.1 ± 15.2 days for patients with and without plasma transfusion, respectively (p = 0.001). ConclusionPlasma transfusion following spontaneous SAH is not uncommon. Although the in-hospital mortality rate does not increase following plasma transfusion, cerebral ischemic events as well as other morbidities are more frequent in patients receiving plasma transfusion. Therefore, the indication for plasma transfusion following SAH needs careful weighing and should be further defined by well-controlled studies.

Multimodal imaging of the role of hyperglycemia following experimental subarachnoid hemorrhage

Hyperglycemia has been linked to worsening outcomes after subarachnoid hemorrhage (SAH). Nevertheless, the mechanisms involved in the pathogenesis of SAH have been scarcely evaluated so far. The role of hyperglycemia was assessed in an experimental model of SAH by T2 weighted, dynamic contrast-enhanced magnetic resonance imaging (T2W and DCE-MRI), [18F]BR-351 PET imaging and immunohistochemistry. Measures included the volume of bleeding, the extent of cerebral infarction and brain edema, blood brain barrier disruption (BBBd), neutrophil infiltration and matrix metalloprotease (MMP) activation. The neurofunctional outcome, neurodegeneration and myelinization were also investigated. The induction of hyperglycemia increased mortality, the size of the ischemic lesion, brain edema, neurodegeneration and worsened neurological outcome during the first 3 days after SAH in rats. In addition, these results show for the first time the exacerbating effect of hyperglycemia on in vivo MMP activation, Intercellular Adhesion Molecule 1 (ICAM-1) expression and neutrophil infiltration together with increased BBBd, bleeding volume and fibrinogen accumulation at days 1 and 3 after SAH. Notably, these data provide valuable insight into the detrimental effect of hyperglycemia on early BBB damage mediated by neutrophil infiltration and MMP activation that could explain the worse prognosis in SAH.

MicroRNAs' Role in Diagnosis and Treatment of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is most commonly seen in patients over 55 years of age and often results in a loss of many productive years. SAH has a high mortality rate, and survivors often suffer from early and secondary brain injuries. Understanding the pathophysiology of the SAH is crucial in identifying potential therapeutic agents. One promising target for the diagnosis and prognosis of SAH is circulating microRNAs, which regulate gene expression and are involved in various physiological and pathological processes. In this review, we discuss the potential of microRNAs as a target for diagnosis, treatment, and prognosis in SAH.

Relationship between Peripheral Blood Inflammatory Factors and Prognosis of Subarachnoid Hemorrhage: A Meta-Analysis

Introduction: Subarachnoid hemorrhage (SAH) is a severe cerebrovascular event with high mortality and disability rate. Neuroinflammation is involved in the brain injury after SAH, but the exact association between SAH progression and peripheral blood inflammatory factors is unknown. Therefore, to determine the relationship between inflammatory factors and the prognosis of SAH, we performed a meta-analysis. Method: A systematic literature review was conducted in PubMed, Embase, and the Cochrane Library. Studies comparing the relationship between inflammatory factors (C-reactive protein [CRP], interleukin-6 [IL-6], interleukin-10 [IL-10], and tumor necrosis factor [TNF-α]) and prognosis of SAH were included in the study. A random-effects meta-analysis was conducted based on mRS, GOS, and the occurrence of cerebral vasospasm, delayed cerebral ischemia, and delayed ischemic neurologic deficits. Sensitivity analysis was performed using the leave-one-out method. The Newcastle-Ottawa Scale (NOS) for case-control studies was used to assess the quality of included studies. For continuous variables, we calculated the mean difference with a 95% confidence interval (CI). Results: 1,469 patients from 18 case-control studies met the inclusion criteria. The results found that patients in the good outcome group had significantly lower CRP levels than those in the poor outcome group (SMD: −1.15, 95% CI: −1.64 to −0.66, p < 0.00001, I2 = 87%), and peripheral IL-6 levels were significantly lower in SAH patients with the good functional outcome than those with the poor functional outcome (SMD: −0.99, 95% CI: −1.48 to −0.51, p < 0.0001, I2 = 88%). As for IL-10 (SMD: −0.28, 95% CI: −0.97 to 0.42, p = 0.43, I2 = 88%) and TNF-α (SMD: −0.40, 95% CI: −0.98 to 0.19, p = 0.18, I2 = 79%), due to the small number of studies, heterogeneity, and uncontrollable factors, robust conclusions cannot be drawn. Conclusion: SAH patients with good prognoses have significantly lower peripheral CRP and IL-6 levels. In addition, due to the small number of studies, heterogeneity, and uncontrollable factors, robust conclusions cannot be drawn for IL-10 and TNF-α. More high-quality studies are needed in the future to provide more specific recommendations for the clinical practice of inflammatory factors.

Elevated levels of several chemokines in the cerebrospinal fluid of patients with subarachnoid hemorrhage are associated with worse clinical outcome.

Chemokines are small cytokines that exert chemotactic actions on immune cells and are involved in many inflammatory processes. The present study aims to provide insight in the role of this relatively unexplored family of proteins in the inflammatory pathophysiology of subarachnoid hemorrhage (SAH). Cerebrospinal fluid of 29 patients (17 female; mean age 57 years) was collected at days 1, 4 and 10 after SAH, centrifuged and frozen at -70°C. Analysis of 92 inflammation-related proteins was performed using Target 96 Inflammation ® assay (Olink Proteomics, Uppsala, Sweden) based on Proximity Extension Assay technology. The panel included 20 chemokines (CCL2 (or MCP-1), CCL3, CCL4, CCL7 (or MCP-3), CCL8 (or MCP-2), CCL11 (or Eotaxin), CCL13 (or MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CXCL1, CXCL5, CXCL6, CXCL8 (or IL-8), CXCL9, CXCL10, CXCL11 and CX3CL1 (or Fractalkine)) that were analyzed for their temporal patterns of expression and compared in dichotomized clinical groups based on World Federation of Neurosurgical Societies (WFNS) admission score and amount of blood on admission CT based on Fisher scale; presence of delayed cerebral ischemia(DCI)/delayed ischemic neurological deficit (DIND); and clinical outcome based on Glasgow Outcome Scale. Protein expression levels were provided in output unit Normalized Protein Expression (NPX). ANOVA models were used for statistical analyses. Four temporal patterns of expression were observed (i.e., early, middle, late peak and no peak). Significantly higher day 10 mean NPX values were observed in patients with poor outcome (GOS 1-3) for chemokines CCL2, CCL4, CCL7, CCL11, CCL13, CCL19, CCL20, CXCL1, CXCL5, CXCL6 and CXCL8. In the WFNS 4-5 group, CCL11 showed significantly higher day 4 and day 10 mean NPX values and CCL25 significantly higher day 4 values. In patients with SAH Fisher 4, CCL11 showed significantly higher mean NPX values on days 1, 4 and 10. Finally, patients with DCI/DIND had significantly higher day 4 mean NPX values of CXCL5. Higher levels of multiple chemokines at the late stage of SAH seemed to correlate with worse clinical outcome. A few chemokines correlated with WFNS score, Fisher score and occurrence of DCI/DIND. Chemokines may be useful as biomarkers for describing the pathophysiology and prognosis of SAH. Further studies are needed to better understand their exact mechanism of action in the inflammatory cascade.

Association of Gut Microbiome with Early Brain Injury After Subarachnoid Hemorrhage: an Experimental Study.

The occurrence of early brain injury (EBI) following subarachnoid hemorrhage (SAH) is crucial in the prognosis of SAH; however, no effective treatment for EBI has been developed. Gut microbiome (GM) composition influences the outcome of various diseases, including ischemic stroke. Here, we evaluated whether prior GM alteration could prevent EBI following SAH. We altered the GM of 7-week-old male rats by administering antibiotic-containing water for 2weeks and performing fecal microbiome transplantation after antibiotic induction. Composition of the GM was profiled using 16S rRNA. We induced SAH by injecting blood in the subarachnoid space of control rats and rats with altered GM. We evaluated EBI indicators such as neurological score, brain water content, Evans blue extravasation, and neuronal injury. Additionally, we studied inflammatory cells using immunohistochemistry, immunocytochemistry, quantitative PCR, and flow cytometry. EBI was significantly averted by alterations in GM using antibiotics. The altered GM significantly prevented neutrophil infiltration into the brain among inflammatory cells, and this anti-inflammatory effect was observed immediately following SAH onset. The altered GM also prevented neutrophil extracellular trap formation in the brain and blood, indicating the systemic protective effect. The cause of the protective effect was attributed to a significant decrease in aged neutrophils (CXCR4high CD62Llow) by the altered GM. These protective effects against EBI disappeared when the altered GM was recolonized with normal flora. Our findings demonstrated that EBI following SAH is associated with GM, which regulated neutrophil infiltration.

Rapid magnetic separation: An immunoassay platform for the SERS-based detection of subarachnoid hemorrhage biomarkers.

The blood-brain barrier (BBB) is of vital importance to the progression and prognosis of subarachnoid hemorrhage (SAH). The construction of a simple, sensitive, and accurate detection assay for measuring the biomarkers associated with BBB injury is still an urgent need owing to the complex pathogenesis of SAH and low expression levels of pathological molecules. Herein, we introduced surface-enhanced Raman scattering (SERS) label-embedded Fe3O4@Au core-shell nanoparticles as ideal SERS sensors for quantitative double detection of MMP-9 and occludin in SAH patients. Meanwhile, utilizing the SERS signals to dynamically estimate MMP-9 and occludin concentration in the rat SAH model is the first application in exploring the relationship of pathological MMP-9 and occludin molecular levels with neurobehavioral score. This method warrants reliable detection toward MMP-9 and occludin with a wide recognition range and a low detection limit in blood samples. Furthermore, the results monitored by the SERS assay exactly matched with those obtained through a traditional enzyme-linked immunosorbent assay (ELISA). The aforementioned results demonstrated this novel biosensor strategy has extensive application prospects in the quantitative measurement of multiple types of biomolecules in body fluid samples.

The minor allele of rs17427875 in long non-coding RNA-HOXA11-AS influences the prognosis of subarachnoid hemorrhage (SAH) via modulating miR-15a and STAT3 expression

Background: HOAX11-AS was reported to promote the progression of liver cancer via the signaling pathway of miR-15a-3p/STAT3. In this study, we investigated the effect of rs17427875 on the prognosis of subarachnoid hemorrhage (SAH) and its underlying molecular mechanisms.Methods: 158 SAH patients were recruited and grouped according to their genotypes rs17427875. Peripheral blood and cerebrospinal fluid (CSF) samples were collected for subsequent analysis. Quantitative real-time PCR, luciferase assays, Western blot and ELISA were performed to analyze the correlations between the expression of lncRNA-HOXA11-AS, miR-15a, TNF-α and NF-κB.Results: The survival rate was remarkably higher in SAH patients carrying the AA genotype of rs17427875 when compared with those carrying the AT genotype. The expression of miR-15a was significantly repressed in the peripheral blood and CSF of SAH patients carrying the AT allele when compared with that in patients carrying the AA allele. MiR-15a showed a remarkable efficacy in inhibiting the luciferase activity of wild type lncRNA-HOXA11-AS and STAT3 in THP-1 cells. P-HOXA11-AS-T showed a stronger ability to suppress the expression of miR-15a and activate the expression of STAT3, TNF-α and NF-κB in THP-1 cells when compared with P-HOXA11-AS-A.Conclusions: The findings demonstrated that the presence of the minor allele of rs17427875 in lncRNA-HOXA11-AS could increase the expression level of lncRNA-HOXA11-AS, thus elevating the expression level of STAT3 via down-regulating miR-15a, and increased STAT3 expression could aggravate inflammation to cause poor prognosis of SAH. Therefore, the rs17427875 polymorphism can be used as a potential biomarker for the prognosis of SAH.

Inhibition of the myeloid differentiation primary response protein 88 reducres neuron injury in the early stages of subarachnoid hemorrhage in an in vitro experimental model.

Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease with high rates of morbidity and mortality and a paucity of effective therapies. The development of early brain injury (EBI) is closely related to prognosis in SAH, and inflammation plays an important role in its pathophysiology. A previous experiment showed that ST2825, a selective inhibitor of MyD88, could alleviate EBI in vivo. However, this protective effect in vivo is affected by a variety of pathophysiology processes making the result to some extent uncertain. whether there is a coincident result in vitro ruling out the effect of other factors remains unknown, and further investigation using cultured neurons is necessary. Primary neuronal cells were cultured to construct an in vitro model of SAH. The cells were cultured and then divided into three groups: (1) a blank control group, (2) an oxygenated hemoglobin + vehicle group, and (3) an oxygenated hemoglobin + ST2825 group. In each group, apoptosis of neuronal cells along with changes in the expression of proteins including MyD88, p-JNK, p-Erk, p-p38, NFκB, Bcl-2, and P53 were measured. Results showed that after stimulating neurons with oxygenated hemoglobin, the expression of the MyD88 protein in the vehicle group increased significantly. The quantity of p-JNK, p-p38, and p-Erk also increased significantly, as did the quantity of p65 in the nucleus. Expression of the anti-apoptotic protein Bcl-2 was markedly reduced, while that of the cleaved caspase-3 protein was significantly increased. In addition, in this group, the apoptosis rate of neurons was significantly increased. In the ST2825 group, the expression of p-JNK, p-p38, p-Erk, cleaved caspase-3, and p65 in the nucleus was significantly decreased, the expression of Bcl-2 was significantly increased, and the apoptosis rate of neurons was significantly reduced. The results of this study suggest that in an experimental in vitro SAH model, ST2825, a selective inhibitor of MyD88, can have a neuroprotective effect by inhibiting neuronal apoptosis mediated by the MAPK and NFκB signaling pathways, and this has a certain protective effect on EBI after SAH.

Abstract WP236: The Gut Microbiome Is Associated With Early Brain Injury After Experimental Subarachnoid Hemorrhage Via Regulation Of Neutrophils

Background: It is known that early brain injury (EBI), which occurs early after the onset of subarachnoid hemorrhage (SAH), largely determines the prognosis of SAH; however, an effective treatment for EBI has not been developed. The outcome of various diseases including ischemic stroke is influenced by the composition of the gut microbiome (GM) and we have previously shown that the GM is also associated with the rupture of cerebral aneurysms. Here, we studied whether prior alteration of the GM can prevent EBI after SAH. Methods: We altered the GM of 7-week-old male rats by administering antibiotics-containing water for 2 weeks or performing fecal microbiome transplantation after antibiotics treatment. The composition of the GM was profiled using 16S rRNA. SAH was induced by injection of blood in the subarachnoid space of control rats and rats with altered GM. We evaluated EBI indicators such as the neurological score, brain water content, Evans blue extravasation, and neuronal apoptosis. We also studied inflammatory cells using immunohistochemistry, immunocytochemistry, quantitative PCR and flow cytometry. Results: There were significant differences in alpha and beta diversity between the control and antibiotics-treated rats. Compared with the control rats, the antibiotics-treated rats had significantly reduced neurological symptoms, brain edema, blood-brain barrier disruption and apoptosis. Among inflammatory cells, neutrophil infiltration into the brain was significantly reduced in the antibiotics-treated rats. Interestingly, the preventive effect on neutrophil infiltration was already observed immediately after SAH. Next, the immune status of each group before SAH onset was examined. There was no difference in circulating neutrophil counts, but flow cytometry showed a significant decrease in aged neutrophils which exhibit a highly reactive phenotype in the antibiotics-treated rats. Finally, the neuroprotective effect of antibiotics against EBI disappeared when the GM was recolonized. Conclusions: Our findings suggest that the GM affects the severity of EBI after SAH by regulating neutrophils. In the future, adjustment of the GM to prevent EBI may become a new strategy in patients who are being followed for cerebral aneurysms.

Loss of Consciousness at Onset of Subarachnoid Hemorrhage as Marker of Short Term Outcome

Background: Studies assessing the impact of loss of consciousness (LOC) on prognosis of subarachnoid hemorrhage (SAH) has been limited.&#x0D; Objective: This scientific assessment was done to determine the effect of LOC on outcome of SAH.&#x0D; Methodology: This hospital based observational study was done in Department of Neurology of Dhaka Medical College Hospital, Dhaka, Bangladesh from January 2018 to December 2018. Patients with the diagnosis of SAH admitted in the in-patient wards of Neurology, Neurosurgery and Internal Medicine were taken as study population. The patients were divided in two groups with either presence (B) or absence of loss of consciousness (A). Group B was further subdivided into 3 subgroup depending admission WFNS scale grades (BI= WFNS II &amp;III, BII=WFNS IV and BIII=WFNS V). Follow up was done in the stroke clinic, outpatient department of Neurology or by telephone interviews of patients, caregivers or family members. Outcome was measured by modified Rankin Scale (mRS).&#x0D; Result: A total of 75 patients were divided into group A and Group B. Six (8.0%) patients died during hospital stay, 6 died after 3 months. All those died during hospital stay were from group B. At 3 months, 16(21.3%) patients were lost during follow up. In group A at discharge 28.6% patients had poor outcome whereas 36% of patients in group B had poor outcome. Within group B most of the patients having poor outcome were in subgroup BIII (75.0%) compared to 33.0% cases in BI (p=0.023). About 16.7% cases in group A had poor outcome at 3 months and 75.0% cases in Group BIII. Furthermore, 8.3% patients died in Group A, however, 25.0% died in Group BIII. WFNS grade (IV or V) had statistically significant influence on poor outcome among patients having LOC (adjusted Odds ratio is 2.20, p=0.04 and 95% CI 1.03–4.71).&#x0D; Conclusion: Loss of consciousness at onset of SAH is an important marker for p oor outcome.&#x0D; Journal of National Institute of Neurosciences Bangladesh, January 2021, Vol. 7, No. 1, pp. 20-24

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

BackgroundNeuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH.MethodsA total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro.ResultsSTING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro.ConclusionMicroglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.

The value of glial fibrillary acidic protein levels in the diagnosis and prognosis of subarachnoid hemorrhage

Background: Subarachnoid hemorrhages is an important emergency condition due to its high morbidity and mortality. Early diagnosis and rapid intervention are very important to prevent poor clinical outcome of this disease. Objective: The aim of this study was to determine the value of glial fibrillary acidic protein in the diagnosis and prognosis of subarachnoid hemorrhage. Methods: Patients presenting to the emergency department and undergoing computerized tomography and/or lumbar puncture due to suspicion of subarachnoid hemorrhage were included in this prospective study. Based on the computerized tomography–lumbar puncture results, cases were divided into subarachnoid hemorrhage group and non–subarachnoid hemorrhage control group. Subarachnoid hemorrhage patients were classified on the basis of severity of subarachnoid hemorrhage and were classified as good or poor clinical outcome groups based on Glasgow Outcome Scores. Glial fibrillary acidic protein levels were then compared. Results: A total of 111 patients were evaluated due to suspicion of subarachnoid hemorrhage and diagnosed with subarachnoid hemorrhage (n = 73) or without subarachnoid hemorrhage (n = 38). Cerebrospinal fluid glial fibrillary acidic protein levels were significantly higher in the subarachnoid hemorrhage group than in the non–subarachnoid hemorrhage group (p &lt; 0.001) (median (25%–75%): 11.62 (2.64–68.04) and 2.26 (1.5–4.83), respectively). Serum glial fibrillary acidic protein levels of the subarachnoid hemorrhage patients with poor clinical outcomes were higher than those of subarachnoid hemorrhage patients with good clinical outcomes (p = 0.003) and cerebrospinal fluid glial fibrillary acidic protein levels were similar (p = 0.379). Glial fibrillary acidic protein levels at the time of presentation exhibited a low level of correlation with Glasgow coma score, World Federation of Neurological Surgeons scale, Hunter–Hess Scale, Ogilvy–Carter Scale, Glasgow Outcome Score, and modified Rankin score. Conclusion: Cerebrospinal fluid glial fibrillary acidic protein levels may be a valuable diagnostic parameter at the time of presentation for diagnosis of subarachnoid hemorrhage. And also serum glial fibrillary acidic protein levels may be useful in predicting subarachnoid hemorrhage patients with poor clinical outcomes.

Evaluation of the platelet volume index as a prognostic factor after aneurysmal subarachnoid hemorrhage

Aim: Subarachnoid Hemorrhage (SAH) originating from an intracranial aneurysm is a severe and life-threatening disease, witnessed by physicians in Emergency Departments (ED). Despite the improvements in diagnostic and therapeutic techniques, morbidity and mortality rates of SAH remain high. Several parameters based on biochemical analysis and imaging techniques are used to evaluate the prognosis. However, efforts for identifying an ideal marker have not been successful. For many years, Fisher Grading System, which is based on computerized tomography (CT), has been used as a reliable predictive scale to identify SAH. Besides, the immune response plays an active role in determining neuro-damage after SAH. Recently, Mean platelet volume (MPV) to platelet count (PLT) ratio has become a trend indicator to anticipate the outcome of a patient suffering from SAH. This study aims to determine whether the comparison of the immune response marker [Platelet Volume Index (PVI)] with the Fisher Grading System could be used as a prognostic factor in subarachnoid hemorrhages with ruptured intracranial aneurysms.Methods: In this retrospective cohort study, 52 patients diagnosed with spontaneous SAH in the ED were included. The patients’ ages, genders, Fisher grades, locations of the ruptured aneurysm, PVI and Glasgow Coma Scale (GCS) scores were recorded. MPV:PLT ratio was defined as MPV value(fL) x100 /PLT (per 1000). Each patient's GCS at the time of their admission to the ED was noted. An experienced radiologist graded their initial CT scans immediately according to the Fisher Grading System. Patients’ GCS scores were noted by the investigators and PVI was calculated. A retrospective review was carried out regarding medical records of age, sex, and other conditions. The Pearson Correlation Coefficient was used in the analysis of the interrelationship.Results: The correlation among the PVI with GCS and Fisher Grade test was found to be positive statistically correlation. Relevant literature establishes the same result. Additionally, analyses established a significant positive correlation between the Fisher Grading Scale and the PVI among the data of ruptured aneurysms.Conclusion: The PVI can be used as a prognostic, predictive factor for SAH. Nevertheless, further studies concerning the prognosis of SAH are needed to confirm this hypothesis.

17-Allylamino-Demethoxygeldanamycin Ameliorate Microthrombosis Via HSP90/RIP3/NLRP3 Pathway After Subarachnoid Hemorrhage in Rats.

Subarachnoid hemorrhage (SAH) is a severe and emergent cerebrovascular disease, the prognosis of which usually very poor. Microthrombi formation highlighted with inflammation occurs early after SAH. As the main cause of DCI, microthrombosis associated with the prognosis of SAH. The aim of this study was to show HSP90 inhibitor 17-AAG effect on microthrombosis after SAH in rats. Ninety-five SD rats were used for the experiment. For time course study, the rats were randomly divided into five groups: sham group and SAH group with different time point (1d, 2d, 3d, 5d). Endovascular perforation method was conducted for SAH model. Neurological score, SAH grade, and mortality were measured after SAH. The samples of the left hemisphere brain were collected. The expression of HSP90 was detected by Western blot. The microthrombosis after SAH in rats' brain was detected by immunohistochemistry. For mechanism study, rats were randomly divided into three groups: sham, SAH+vehicle, and SAH +17-AAG (n=6/group). 17-AAG was given by intraperitoneal injection (80mg/kg) 1h after SAH. Neurological function were measured at 24 h after SAH. The expression of RIP3, NLRP3, ASC, and IL-1β was measured by Western blot. Microthrombosis was detected by immunohistochemistry. Our results showed that the HSP90 protein level increased and peaked at 2 days after SAH. Microthrombosis caused by SAH was increased in 1day and peaked at 2days after SAH. Administration HSP90 specific inhibitor 17-AAG reduced expression of RIP3, NLRP3, ASC, and IL-1β, reduced microthrombosis after SAH, and improved neurobehavior when compared to vehicle group. 17-AAG can ameliorate microthrombosis via HSP90/RIP3/NLRP3 pathway and improve neurobehavior after SAH.

Bax inhibitor-1 suppresses early brain injury following experimental subarachnoid hemorrhage in rats.

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is an important cause of high mortality and poor prognosis in SAH. B‑cell lymphoma 2‑associated X protein inhibitor‑1 (BI‑1) is an evolutionarily conserved antiapoptotic protein that is primarily located in the membranes of endoplasmic reticulum (ER). BI‑1 has been studied in certain nervous system‑associated diseases, but the role of this protein in SAH remains unclear. In the present study, the role of BI‑1 in EBI following SAH was investigated in rat models and its associated mechanisms were examined. The SAH rat model was generated by inserting nylon cords into the internal carotid artery from the external carotid artery. Samples were assessed using neurological scores, brain water content measurements, hematoxylin and eosin (H&E) staining, blood‑brain barrier (BBB) permeability, terminal deoxynucleotidyl transferase‑mediated dUTP nick‑end labeling and quantitative polymerase chain reaction assays, and western blot analyses. It was identified that the mRNA and protein levels of BI‑1 decreased markedly and were lowest at 24h after SAH. BI‑1 overexpression and small hairpin RNA (shRNA)‑mediated silencing markedly suppressed or severely exacerbated EBI following SAH, respectively. BI‑1 overexpression in the SAH model improved neurological scores and decreased the brain water content, BBB permeability and levels of apoptosis compared with the control and sham groups following SAH. BI‑1 shRNA in the SAH model demonstrated contrary results. In addition, the mRNA or protein expression levels of ER stress‑associated genes (glucose regulated protein, 78 kDa, C/EBP homologous protein, Serine/threonine‑protein kinase/endoribonuclease IRE1, c‑Jun N terminal kinases and apoptotic signaling kinase‑1) were markedly suppressed or increased following BI‑1 overexpression and shRNA‑mediated silencing, respectively. The present study suggested that BI‑1 serves a neuroprotective role in EBI following SAH by attenuating BBB disruption, brain edema and apoptosis mediated by ER stress.

Antioxidant Melatonin: Potential Functions in Improving Cerebral Autoregulation After Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a subtype of stroke with high mortality and morbidity. Impaired cerebral autoregulation following SAH has been reported owing to effects on sympathetic control, endothelial function, myogenic response, and cerebral metabolism. Impaired cerebral autoregulation is associated with early brain injury, cerebral vasospasm/delayed cerebral ischemia, and SAH prognosis. However, few drugs have been reported to improve cerebral autoregulation after SAH. Melatonin is a powerful antioxidant that is effective (easily crosses the blood brain barrier) and safe (tolerated in large doses without toxicity). Theoretically, melatonin may impact the control mechanisms of cerebral autoregulation via antioxidative effects, protection of endothelial cell integrity, suppression of sympathetic nerve activity, increase in nitric oxide bioavailability, mediation of the myogenic response, and amelioration of hypoxemia. Furthermore, melatonin may have a comprehensive effect on cerebral autoregulation. This review discusses the potential effects of melatonin on cerebral autoregulation following SAH, in terms of the association between pharmacological activities and the mechanisms of cerebral autoregulation.

The mechanism and treatment progress of microthrombus in delayed cerebral ischemia after subarachnoid hemorrhage

Delayed cerebral ischemia (DCI) is a severe complication leading to death and disability after subarachnoid hemorrhage (SAH). Cerebral vasospasm (CVS) is generally believed as the main cause of DCI. Recently, increasing studies have demonstrated that SAH-induced activation of inflammation, coagulation or endothelial cells, and even the damage of fibrinolytic cascade may lead to the formation of microthrombus, which may eventually develop into DCI. Autopsy has confirmed the presence microthrombus. Therefore, understanding the mechanism of microthrombus and the role of microthrombus during DCI is crucial for the treatment and prognosis of SAH. Key words: Subarachnoid hemorrhage; Delayed cerebral ischemia; Microthrombus; Vasospasm