RARE DISEASE
Acquired aneurysmal subarachnoid hemorrhage
Acquired aneurysmal subarachnoid hemorrhage
Acquired aneurysmal subarachnoid hemorrhage
Drug discovery
23
drugs
With orphan designations
Overview
Acquired aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening emergency caused by rupture of intracranial aneurysms, leading to bleeding in the subarachnoid space. Key risk factors include hypertension, smoking, and familial predisposition. Clinical features include thunderclap headache, nausea, and neurological deficits. Mortality remains high (prehospital: 22–26%; in-hospital: 13–20%), with survivors often facing long-term neurocognitive deficits. Immediate aneurysm repair and intensive care management are critical to prevent rebleeding and mitigate complications like vasospasm [1][2][6].
Therapies
Aneurysm repair: Endovascular coiling or surgical clipping within 24 hours to prevent rebleeding [1][3].
Vasospasm management: Nimodipine, hemodynamic augmentation (euvolemia, induced hypertension), and endovascular interventions [8][12][16].
Critical care: Blood pressure control (target systolic 130–139 mmHg), seizure prophylaxis, and hydrocephalus management (EVD) [3][12].
Categories: rare neurological diseases
Research Papers
365 drug discovery papers about Acquired aneurysmal subarachnoid hemorrhage, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
365 drug discovery papers about Acquired aneurysmal subarachnoid hemorrhage, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2022-11-23 | Identification of The Unique Subtype of Macrophages in Aneurysm Lesions at the Growth Phase.
Recent experimental studies have defined intracranial aneurysms as a macrophage-mediated chronic inflammatory disease affecting intracranial arteries. Although there are various subtypes in macrophages, what type of macrophages is present in lesions during the disease development remains to be elucidated. The previously-established aneurysm model of rats was used. Macrophages were labeled with the fluorescent protein and isolated by a laser-microdissection method. The comprehensive gene expression profile analyses and gene ontology analyses was then done to identify a macrophage subtype present in lesions at the growth phase. The gene expression profile data of total 52 macrophages infiltrating into the lesions was acquired. The principal component analysis revealed the monotonous macrophage subtype. By comparing the profile identified with one from in vitro-differentiated M0 or M1 macrophages, the macrophages in the lesions were belonged to the simple and unique subtype. Because the perception of signaling from nervous system was highlighted as up-represented terms through gene ontology analyses, the macrophage subtype in lesions at the growth phase might be differentiated under the influence of nervous system in the microenvironment. The histopathological examinations supported the above notion by confirming the presence of nerves in the adventitia. The findings from the present study have provided the useful insights about the macrophage subtype in aneurysm lesions at the growth phase and also proposed its ability as a therapeutic target.
2022-10-01 | Dental Pulp Stem Cell-Derived Conditioned Medium Alleviates Subarachnoid Hemorrhage-Induced Microcirculation Impairment by Promoting M2 Microglia Polarization and Reducing Astrocyte Swelling
Aneurysmal subarachnoid hemorrhage (SAH) can cause severe neurological deficits and high mortality. Early brain edema following SAH contributes to the initiation of microcirculation impairment and may further lead to delayed ischemic neurologic deficit (DIND). This study aimed to investigate whether dental pulp stem cell conditioned medium (DPSC-CM) ameliorates SAH-induced microcirculation impairment and the underlying mechanisms. SAH was induced via intrathecal injection of fresh autologous blood in Wistar male adult rat. DPSC-CM or DPSC-CM + insulin growth factor-1 (IGF-1) antibody was randomly administered by intrathecal route 5 min after SAH induction. To evaluate the underlying mechanisms of DPSC-CM in the treatment of SAH, primary rat astrocyte and microglia co-cultures were challenged with hemolysate or SAH-patient CSF in the presence or absence of DPSC-CM. The results showed that in vivo, DPSC-CM treatment decreased the brain water content, improved microcirculation impairment and enhanced functional recovery at 24 h post-SAH. DPSC-CM treatment also alleviated the expressions of water channel protein aquaporin-4 (AQP4) and pro-inflammatory cytokines, and enhanced the expressions of anti-inflammatory factors in the cortical region. However, all the beneficial effects of DPSC-CM were abrogated after treatment with IGF-1 neutralizing antibody. The in vitro results further showed that DPSC-CM treatment reduced hemolysate/SAH-patient CSF-induced astrocyte swelling and promoted M2 microglia polarization, partially through IGF-1/AKT signaling. The data suggested that DPSC-CM significantly reduced brain edema and rescued microcirculation impairment with concomitant anti-inflammatory benefits after SAH, and may potentially be developed into a novel therapeutic strategy for SAH.
2018-07-07 | Endothelial Cell Dysfunction and Injury in Subarachnoid Hemorrhage
In the brain, vascular endothelial cells conserve blood viscosity, control blood flow, and form the interface between central nervous system and circulating blood. Clinical outcome after aneurysmal subarachnoid hemorrhage is linked to early brain injury, cerebral vasospasm, and other causes of delayed cerebral ischemia. The cerebral vasculature remains a unique target for therapies since it becomes rapidly disrupted after subarachnoid hemorrhage, and damage to the blood vessels continues into the delayed injury phase. The current failure of therapies to improve clinical outcome warrants a re-evaluation of current therapeutic approaches. The mechanisms of endothelial cell injury and blood–brain barrier breakdown are critical to the pathway of cerebral injury, and an improved understanding of these mechanisms may lead to novel therapeutic targets. This review provides an update on the current understanding of endothelial cell injury following aneurysmal subarachnoid hemorrhage, including blood–brain barrier dysfunction.
2014-02-28 | Therapeutic Benefit of Bone Marrow–Derived Endothelial Progenitor Cell Transplantation after Experimental Aneurysm Embolization with Coil in Rats
Aneurysm embolization with coil is now widely used clinically. However, the recurrence of aneurysms after embolization has always plagued neurosurgeons because the endothelial layer of the aneurysm neck loses its integrity after being embolized by coil. Bone marrow–derived endothelial progenitor cells (BM-EPCs) could be incorporated into injured endothelium and differentiate into mature endothelial cells during vascular repairing processes. The aim of our study is to explore the effects of BM-EPCs on aneurysm repairing and remodeling in a rat embolization model of abdominal aortic aneurysm. BM-EPC proliferation, migration and tube formation were not affected by super-paramagnetic iron oxide nanoparticle (SPIO) labeling compared to the controls (p>0.05). The number of SPIO-labeled cells greatly increased in EPC transplanted rats compared to that of phosphate buffered saline treated rats. SPIO-labeled EPC (SPIO-EPC) are mainly located in the aneurysm neck and surrounded by fibrous tissue. A histology study showed that the aneurysm orifice was closed with neointima and the aneurysm was filled with newly formed fibrous tissue. The SPIO-EPC accumulated in the aneurysm neck, which accelerated focal fibrous tissue remodeling, suggesting that BM-EPCs play a crucial role in repairing and remodeling the aneurysm neck orifice.
1996-09-01 | Management of Nontraumatic Subarachnoid Hemorrhage in a Patient with Sickle‐cell Disease: A Case Report
Subarachnoid hemorrhage (SAH) due to sickle-cell anemia is rare, but potentially devastating. However, with early recognition of SAH, aggressive support with exchange transfusion, cerebral angiography, and neurosurgical intervention, a positive outcome may be achieved. A case report of SAH managed in this fashion is reported. Based on similar cases in the literature, a suggested treatment protocol is provided for the management of nontraumatic SAH in sickle-cell patients presenting to the ED.
antibodies
2024-05-23 | Modulation of the Immunological Milieu in Acute Aneurysmal Subarachnoid Hemorrhage: The Potential Role of Monocytes Through CXCL10 Secretion.
Emerging evidence indicates that aneurysmal subarachnoid hemorrhage (aSAH) elicits a response from both innate and adaptive immune systems. An upregulation of CD8 + CD161 + cells has been observed in the cerebrospinal fluid (CSF) after aSAH, yet the precise role of these cells in the context of aSAH is unkown. CSF samples from patients with aSAH and non-aneurysmal SAH (naSAH) were analyzed. Single-cell RNA sequencing (scRNAseq) was performed on CD8 + CD161 + sorted samples from aSAH patients. Cell populations were identified using "clustering." Gene expression levels of ten previously described genes involved in inflammation were quantified from aSAH and naSAH samples using RT-qPCR. The study focused on the following genes: CCL5, CCL7, APOE, SPP1, CXCL8, CXCL10, HMOX1, LTB, MAL, and HLA-DRB1. Gene clustering analysis revealed that monocytes, NK cells, and T cells expressed CD8 + CD161 + in the CSF of patients with aSAH. In comparison to naSAH samples, aSAH samples exhibited higher mRNA levels of CXCL10 (median, IQR = 90, 16-149 vs. 0.5, 0-6.75, p = 0.02). A trend towards higher HMOX1 levels was also observed in aSAH (median, IQR = 12.6, 9-17.6 vs. 2.55, 1.68-5.7, p = 0.076). Specifically, CXCL10 and HMOX1 were expressed by the monocyte subpopulation. Monocytes, NK cells, and T cells can potentially express CD8 + CD161 + in patients with aSAH. Notably, monocytes show high levels of CXCL10. The elevated expression of CXCL10 in aSAH compared to naSAH indicates its potential significance as a target for future studies.
2024-04-04 | The Role of Tnf and Soluble Tnf Receptors (TNFR1/2) as Therapeutic Targets for Inflammation Secondary to Intracerebral Stroke and Hemorrhage
Most neurodegenerative diseases, including Alzheimer's disease, ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage are associated with inflammation. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine that regulates cerebral infarction in stroke pathology, and its action is influenced by the bioavailability of its membrane-bound receptors, TNFR1 and TNFR2, and microglial activation. During the initial onset of these diseases, the soluble variant of the cytokine presents with prolonged and excessive activation of TNFR1, resulting in cell death and long-term neurological impairments. Therapeutic interventions for neurodegenerative diseases have targeted TNF to limit the onset of neuroinflammation. First-generation therapeutics have been demonstrated to inhibit membrane-bound TNF to TNFR2 receptor binding, resulting in severe side effects such as infections and cancer. As such, second-generation drugs, including XPro1595, have been developed to selectively inhibit soluble TNF and impede the effects of TNFR1 while still allowing for TNFR2 activation. Early results in murine TBI models demonstrate reduced glial reactivity by 50%, reduced dendritic degeneration by 30%, increased plasticity by 15%, and improved functional outcomes by 20% post-TBI. This scoping review of TNF receptors in various neurodegenerative diseases seeks to evaluate current and future therapeutic strategies as well as highlight potential strategies to eliminate confounding variables present in the current literature.
2023-05-21 | Single‐Cell RNA Sequencing and Spatial Transcriptomics Reveal Pathogenesis of Meningeal Lymphatic Dysfunction after Experimental Subarachnoid Hemorrhage
Abstract Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke with high mortality and disability rate. Meningeal lymphatic vessels (mLVs) are a newly discovered intracranial fluid transport system and are proven to drain extravasated erythrocytes from cerebrospinal fluid into deep cervical lymph nodes after SAH. However, many studies have reported that the structure and function of mLVs are injured in several central nervous system diseases. Whether SAH can cause mLVs injury and the underlying mechanism remain unclear. Herein, single‐cell RNA sequencing and spatial transcriptomics are applied, along with in vivo / vitro experiments, to investigate the alteration of the cellular, molecular, and spatial pattern of mLVs after SAH. First, it is demonstrated that SAH induces mLVs impairment. Then, through bioinformatic analysis of sequencing data, it is discovered that thrombospondin 1 (THBS1) and S100A6 are strongly associated with SAH outcome. Furthermore, the THBS1‐CD47 ligand‐receptor pair is found to function as a key role in meningeal lymphatic endothelial cell apoptosis via regulating STAT3/Bcl‐2 signaling. The results illustrate a landscape of injured mLVs after SAH for the first time and provide a potential therapeutic strategy for SAH based on mLVs protection by disrupting THBS1 and CD47 interaction.
2019-12-01 | Innate immunity activation in the early brain injury period following subarachnoid hemorrhage
Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Inflammation is induced following SAH, but the exact role and phenotype of innate immune cells remain poorly characterized. We investigated the inflammatory components of the early brain injury in an animal model and in SAH patients.SAH was induced through injection of blood in the subarachnoid space of C57Bl/6 J wild-type mice. Prospective blood collections were obtained at 12 h, days 1, 2, and 7 to evaluate the systemic inflammatory consequences of SAH by flow cytometry and enzyme-linked immunosorbent-assay (ELISA). Brains were collected, enzymatically digested, or fixed to characterize infiltrating inflammatory cells and neuronal death using flow cytometry and immunofluorescence. Phenotypic evaluation was performed at day 7 using the holding time and footprint tests. We then compared the identified inflammatory proteins to the profiles obtained from the plasma of 13 human SAH patients.Following SAH, systemic IL-6 levels increased rapidly, whereas IL-10 levels were reduced. Neutrophils were increased both in the brain and in the blood reflecting local and peripheral inflammation following SAH. More intracerebral pro-inflammatory monocytes were found at early time points. Astrocyte and microglia activation were also increased, and mice had severe motor deficits, which were associated with an increase in the percentage of caspase-3-positive apoptotic neurons. Similarly, we found that IL-6 levels in patients were rapidly increased following SAH. ICAM-1, bFGF, IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes. Moreover, high levels of Flt-1 and VEGF at admission were associated with worse outcomes.SAH induces an early intracerebral infiltration and peripheral activation of innate immune cells. Furthermore, microglia and astrocytic activation are present at later time points. Our human and mouse data illustrate that SAH is a systemic inflammatory disease and that immune cells represent potential therapeutic targets to help this population of patients in need of new treatments.
2018-11-30 | Inflammatory Smooth Muscle Cells Induce Endothelial Cell Alterations to Influence Cerebral Aneurysm Progression via Regulation of Integrin and VEGF Expression
Cerebral aneurysm growth is characterized by vessel wall frailness, although the underlying cellular mechanisms are unclear. Here, we examined the relationship between inflammatory smooth muscle cells (SMCs) and endothelial cells (ECs) in cerebral aneurysms, including the mechanisms underlying inflammatory SMC-induced changes in ECs. Five saccular cerebral aneurysms were collected and five temporal artery samples were used as controls. Cells and cytokines were detected by immunohistochemistry and TUNEL (transferase dUTP nick end labeling) assays performed to evaluate apoptosis. Human umbilical vein endothelial cells (HUVECs) were seeded on collagen I, IV, and VI-coated plates for cell adhesion assays and inflammatory SMCs (iSMCs) were established by culture in flexible silicone chambers subjected to cyclic mechanical stretch. HUVECs were cultured in iSMC-conditioned medium, followed by evaluation of their viability, apoptosis, and function, and determination of VEGF (vascular endothelial growth factor) -A and integrin levels by western blotting. Aneurysm tissue contained fewer SMCs and lacked ECs. In aneurysm walls, more matrix metalloproteinase (MMP) -1, MMP-3, and apoptotic cells were detected, accompanied by decreased collagen IV and VI levels. Cell adhesion assays revealed that more HUVECs were attached in collagen IV and VI-coated plates compared with controls. iSMC-conditioned medium significantly reduced HUVEC viability and apoptosis showed an increased trend; however, the difference was not significant. iSMC medium also reduced tube formation and migration of HUVECs. Moreover, iSMC medium reduced HUVEC expression of VEGF-A, integrin α1, integrin α2, and integrin β. Our data demonstrate a lack of SMCs and ECs in aneurysm walls, accompanied by elevated MMP and decreased collagen levels. In vitro assays showed that iSMCs induced reduction in EC adhesion, and caused EC dysfunction. Understanding of the relationships among SMC, EC, and collagens during aneurysm progression provides an additional therapeutic option for prevention of cerebral aneurysm progression.
small molecules
2024-06-11 | Oxygen-based autoregulation indices associated with clinical outcomes and spreading depolarization in aSAH
Background Impairment in cerebral autoregulation has been proposed as a potentially targetable factor in patients with aneurysmal subarachnoid hemorrhage (aSAH), however there are different continuous measures that can be used to calculate the state of autoregulation. In addition, it has previously been proposed that there may be an association of impaired autoregulation with the occurrence of spreading depolarization (SD) events. Methods Subjects with invasive multimodal monitoring and aSAH were enrolled in an observational study. Autoregulation indices were prospectively calculated from this database as a 10 second moving correlation coefficient between various cerebral blood flow (CBF) surrogates and mean arterial pressure (MAP). In subjects with subdural ECoG (electrocorticography) monitoring, SD was also scored. Associations between clinical outcomes using the mRS (modified Rankin Scale) and occurrence of either isolated or clustered SD was assessed. Results 320 subjects were included, 47 of whom also had ECoG SD monitoring. As expected, baseline severity factors such as mFS and WFNS (World Federation of Neurosurgical Societies scale) were strongly associated with the clinical outcome. SD probability was related to blood pressure in a triphasic pattern with a linear increase in probability below MAP of ~ 100mmHg. Autoregulation indices were available for intracranial pressure (ICP) measurements (PRx), PbtO2 from Licox (ORx), perfusion from the Bowman perfusion probe (CBFRx), and cerebral oxygen saturation measured by near infrared spectroscopy (OSRx). Only worse ORx and OSRx were associated with worse clinical outcomes. ORx and OSRx also were found to both increase in the hour prior to SD for both sporadic and clustered SD. Conclusions Impairment in autoregulation in aSAH is associated with worse clinical outcomes and occurrence of SD when using ORx and OSRx. Impaired autoregulation precedes SD occurrence. Targeting the optimal MAP or cerebral perfusion pressure in patients with aSAH should use ORx and/or OSRx as the input function rather than intracranial pressure.
2024-04-14 | Taurine ameliorates sensorimotor function by inhibiting apoptosis and activating A2 astrocytes in mice after subarachnoid hemorrhage
Abstract Subarachnoid hemorrhage (SAH) is a form of severe acute stroke with very high mortality and disability rates. Early brain injury (EBI) and delayed cerebral ischemia (DCI) contribute to the poor prognosis of patients with SAH. Currently, some researchers have started to focus on changes in amino acid metabolism that occur in brain tissues after SAH. Taurine is a sulfur-containing amino acid that is semi-essential in animals, and it plays important roles in various processes, such as neurodevelopment, osmotic pressure regulation, and membrane stabilization. In acute stroke, such as cerebral hemorrhage, taurine plays a neuroprotective role. However, the role of taurine after subarachnoid hemorrhage has rarely been reported. In the present study, we established a mouse model of SAH. We found that taurine administration effectively improved the sensorimotor function of these mice. In addition, taurine treatment alleviated sensorimotor neuron damage and reduced the proportion of apoptotic cells. Furthermore, taurine treatment enhanced the polarization of astrocytes toward the neuroprotective phenotype while inhibiting their polarization toward the neurotoxic phenotype. This study is the first to reveal the relationship between taurine and astrocyte polarization and may provide a new strategy for SAH research and clinical treatment.
2024-03-19 | The Role of Epigenetics in Brain Aneurysm and Subarachnoid Hemorrhage: A Comprehensive Review
This comprehensive review explores the emerging field of epigenetics in intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (aSAH). Despite recent advancements, the high mortality of aSAH needs an understanding of its underlying pathophysiology, where epigenetics plays a crucial role. This review synthesizes the current knowledge, focusing on three primary epigenetic mechanisms: DNA methylation, non-coding RNA (ncRNA), and histone modification in IA and aSAH. While DNA methylation studies are relatively limited, they suggest a significant role in the pathogenesis and prognosis of IA and aSAH, highlighting differentially methylated positions in genes presumably involved in these pathologies. However, methodological limitations, including small sample sizes and a lack of diverse population studies, temper these results. The role of ncRNAs, particularly miRNAs, has been more extensively studied, but there are still few studies focused on histone modifications. Despite methodological challenges and inconsistent findings, these studies underscore the involvement of miRNAs in key pathophysiological processes, including vascular smooth muscle regulation and the inflammatory response. This review emphasizes methodological challenges in epigenetic research, advocating for large-scale epigenome-wide association studies integrating genetic and environmental factors, along with longitudinal studies. Such research could unravel the complex mechanisms behind IA and aSAH, guiding the development of targeted therapeutic approaches.
2024-03-13 | Neuroradiological diagnosis and therapy of cerebral vasospasm after subarachnoid hemorrhage
Background Cerebral damage after aneurysmal subarachnoid hemorrhage (SAH) results from various, sometimes unrelated causes. After the initial hemorrhage trauma with an increase in intracranial pressure, induced vasoconstriction, but also microcirculatory disturbances, inflammation and pathological electrophysiological processes (cortical spreading depolarization) can occur in the course of the disease, resulting in delayed cerebral ischemia (DCI). In the neuroradiological context, cerebral vasospasm (CVS) remains the focus of diagnostic imaging and endovascular therapy as a frequent component of the genesis of DCI. Methods The amount of blood leaked during aneurysm rupture (which can be detected by CT, for example) correlates with the occurrence and severity of CVS. CT perfusion is then an important component in determining the indication for endovascular spasm therapies (EST). These include intra-arterial drug administration (also as long-term microcatheter treatment) and mechanical procedures (balloon angioplasty, vasodilatation using other instruments such as stent retrievers, stenting). Conclusion This review summarizes the current findings on the diagnosis and treatment of CVS after aneurysmal SAH from a neuroradiological perspective, taking into account the complex and up-to-date international literature. Key Points Citation Format
2024-01-30 | Endovascular complications: Antiplatelet management for flow diversion
Up to 3−5% of the general population is affected by cerebral aneurysms that are associated with both modifiable as well as non-modifiable risk factors ranging from familial to acquired neurovascular conditions. The initial treatment option was aneurysm clipping and evolved to including primary or adjuvant endovascular treatment. Aneurysm re-rupture, although rare, can have devastating consequences such as intracranial bleeding and carotidcavernous fistula. Emergent surgery in view of delayed aneurysm rupture in patients maintained on dual antiplatelet therapy presents with the need to carefully assess the procedure-related risk factors and evaluate the patients’ platelet function. With the advent of novel technology, flow diverters came into play. These devices utilize the deployment of metallic stents into the parent artery that serves the diversion of blood flow away from the pouching aneurysm. Despite their efficacy, flow diverter insertion and catheter manipulation come with a risk of developing ischemia and stroke, hemorrhage and aneurysm re-rupture, in-stent thrombosis and stenosis, and aneurysmal occlusion amongst other complications. The prospect of thromboembolic events necessitates the use of aggressive antiplatelet regimen with the dual antiplatelet regimen utilizing clopidogrel and aspirin used most frequently. Prasugrel and Ticagrelor have been shown to be superior to Clopidogrel in terms of thromboembolic consequences in cardiovascular literature. Given their potential benefit over the current standard of treatment in this patient population, more extensive randomized-controlled studies are warranted for the evaluation of the efficacy and non-inferiority of Prasugrel and Aspirin or Ticagrelor and Aspirin to Clopidogrel and Aspirin.
proteins
2024-11-28 | Multi-targeted olink proteomics analyses of cerebrospinal fluid from patients with aneurysmal subarachnoid hemorrhage.
The complexity of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) may require the simultaneous analysis of variant types of protein biomarkers to describe it more accurately. In this study, we analyzed for the first time the alterations of cerebrospinal fluid (CSF) proteins in patients with aSAH by multi-targeted Olink proteomics, aiming to reveal the pathophysiology of DCI and provide insights into the diagnosis and treatment of aSAH. Six aSAH patients and six control patients were selected, and CSF samples were analyzed by Olink Proteomics (including 96-neurology panel and 96-inflammation panel) based on Proximity Extension Assay (PEA). Differentially expressed proteins (DEPs) were acquired and bioinformatics analysis was performed. PCA analysis revealed better intra- and inter-group reproducibility of CSF samples in the control and aSAH groups. 23 neurology-related and 31 inflammation-relevant differential proteins were identified. In the neurology panel, compared to controls, the up-regulated proteins in the CSF of SAH patients predominantly included macrophage scavenger receptor 1 (MSR1), siglec-1, siglec-9, cathepsin C (CTSC), cathepsin S (CTSS), etc. Meanwhile, in the inflammation group, the incremental proteins mainly contained interleukin-6 (IL-6), MCP-1, CXCL10, CXCL-9, TRAIL, etc. Cluster analysis exhibited significant differences in differential proteins between the two groups. GO function enrichment analysis hinted that the differential proteins pertinent to neurology in the CSF of SAH patients were mainly involved in the regulation of defense response, vesicle-mediated transport and regulation of immune response; while the differential proteins related to inflammation were largely connected with the cellular response to chemokine, response to chemokine and chemokine-mediated signaling pathway. Additionally, in the neurology panel, KEGG enrichment analysis indicated that the differential proteins were significantly enriched in the phagosome, apoptosis and microRNAs in cancer pathway. And in the inflammation panel, the differential proteins were mainly enriched in the chemokine signaling pathway, viral protein interaction with cytokine and cytokine receptor and toll-like receptor signaling pathway. These identified differential proteins reveal unique pathophysiological characteristics secondary to aSAH. Further characterization of these proteins and aberrant pathways in future research could enable their application as potential therapeutic targets and biomarkers for DCI after aSAH.
2023-07-13 | Circulating Inflammatory Biomarkers and Risk of Intracranial Aneurysm: A Mendelian Randomization Study
Abstract Background Intracranial aneurysm (IA) accounts for a substantial source of non-traumatic subarachnoid hemorrhage, with inflammation postulated as a potential factor in its pathogenesis. The present study aims at evaluating the association between circulating inflammatory cytokines and risk of IA under a bidirectional two-sample Mendelian randomization (MR) design. Methods For primary analysis, summary statistics of inflammatory regulators was obtained from a genome-wide association study (GWAS) comprising 8,293 Finnish participants. Summary data of IA was extracted from a GWAS which comprised 7,495 cases and 71,934 controls in European descent. For targeted analysis, summary statistics were extracted from two proteomic studies, which recruit 3,301 and 5,368 European participants, respectively. Summary data of IA were acquired from FinnGen study with 5,342 cases and 342,673 controls. We employed inverse variance weighted (IVW) method as main approach, with sensitivity analyses using weighted median, MR-Egger, and MR-PRESSO methods. Reverse MR analyses were conducted to minimize bias from reverse causality. Results No causation of cytokines with IA was identified in both primary and targeted analysis after Bonferroni correction. In primary analysis, vascular endothelial growth factor (VEGF) and fibroblast growth factor basic (bFGF) levels were suggestively associated with IA [(VEGF→IA: odds ratio (OR) = 1.11, 95% confidence interval (95% CI) = 1.02–1.20, P = 0.01; bFGF→IA: OR = 0.68, 95% CI = 0.48–0.96, P = 0.03]. Statistical significance failed to replicate in targeted analysis. Instead, suggestive protective effects for aneurysmal subarachnoid hemorrhage (aSAH) were identified in FGF-9 (FGF-9→aSAH: OR = 0.74, 95% CI = 0.62–0.89, P = 0.001) and FGF-16 (FGF-16→aSAH: OR = 0.84, 95% CI = 0.72–0.97, P = 0.017). Furthermore, reverse analyses identified suggestive effect of IA and its subtypes on IL-10, RANTES, MIF, GRO-alpha, FGF-16, and FGF-19. Result remained robust after applying sensitivity tests. Conclusions Our study provided novel insights into the potential protective role of FGF-9 and FGF-16 in aSAH. Future studies are in need to evaluate the temporal dynamics of cytokines in conjunction with IA.
2023-03-27 | Narrative review of roles of astrocytes in subarachnoid hemorrhage
Background and Objective: Astrocytes play an important role in healthy brain function, including the development and maintenance of blood-brain barrier (BBB), structural support, brain homeostasis, neurovascular coupling and secretion of neuroprotective factors.Reactive astrocytes participate in various pathophysiology after subarachnoid hemorrhage (SAH) including neuroinflammation, glutamate toxicity, brain edema, vasospasm, BBB disruption, cortical spreading depolarization (SD).Methods: We searched PubMed up to 31 May, 2022 and evaluated the articles for screening and inclusion for subsequent systemic review.We found 198 articles with the searched terms.After exclusion based on the selection criteria, we selected 30 articles to start the systemic review. Key Content and Findings:We summarized the response of astrocytes induced by SAH.Astrocytes are critical for brain edema formation, BBB reconstruction and neuroprotection in the acute stage of SAH.Astrocytes clear extracellular glutamate by increasing the uptake of glutamate and Na + /K + ATPase activity after SAH.Neurotrophic factors released by astrocytes contribute to neurological recovery after SAH.Meanwhile, Astrocytes also form glial scars which hinder axon regeneration, produce proinflammatory cytokines, free radicals, and neurotoxic molecules.Conclusions: Preclinical studies showed that therapeutic targeting the astrocytes response could have a beneficial effect in ameliorating neuronal injury and cognitive impairment after SAH.Clinical trials and preclinical animal studies are still urgently needed in order to determine where astrocytes stand in various pathway of brain damage and repair after SAH and, above all, to develop therapeutic approaches which benefit patient outcomes.
2021-02-09 | ANGPTL6 Genetic Variants Are an Underlying Cause of Familial Intracranial Aneurysms.
To understand the role of the angiopoietin-like 6 gene (ANGPTL6) in intracranial aneurysms (IAs), we investigated its role in a large cohort of familial IAs.Individuals with family history of IA were recruited to the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study. The ANGPTL6 gene was sequenced using Sanger sequencing. Identified genetic variants were compared to a control population.We found 6 rare ANGPTL6 genetic variants in 9/275 individuals with a family history of IA (3.3%) (5 missense mutations and 1 nonsense mutation leading to a premature stop codon), none present in controls. One of these had been previously reported: c.392A>T (p.Glu131Val) on exon 2; another was very close: c.332G>A (p.Arg111His). Two further genetic variants lie within the fibrinogen-like domain of the ANGPTL6 gene, which may influence function or level of the ANGPTL6 protein. The last 2 missense mutations lie within the coiled-coil domain of the ANGPTL6 protein. All genetic variants were well conserved across species.ANGPTL6 genetic variants are an important cause of IA. Defective or lack of ANGPTL6 protein is therefore an important factor in blood vessel proliferation leading to IA; dysfunction of this protein is likely to cause abnormal proliferation or weakness of vessel walls. With these data, not only do we emphasize the importance of screening familial IA cases for ANGPTL6 and other genes involved in IA, but also highlight the ANGPTL6 pathway as a potential therapeutic target.This is a Class III study showing some specificity of presence of the ANGPTL6 gene variant as a marker of familial intracranial aneurysms in a small subset of individuals with familial aneurysms.
2020-11-17 | Involvement of neutrophils in machineries underlying the rupture of intracranial aneurysms in rats
Subarachnoid hemorrhage due to rupture of an intracranial aneurysm has a quite poor prognosis after the onset of symptoms, despite the modern technical advances. Thus, the mechanisms underlying the rupture of lesions should be clarified. To this end, we obtained gene expression profile data and identified the neutrophil-related enriched terms in rupture-prone lesions using Gene Ontology analysis. Next, to validate the role of neutrophils in the rupture of lesions, granulocyte-colony stimulating factor (G-CSF) was administered to a rat model, in which more than half of induced lesions spontaneously ruptured, leading to subarachnoid hemorrhage. As a result, G-CSF treatment not only increased the number of infiltrating neutrophils, but also significantly facilitated the rupture of lesions. To clarify the mechanisms of how neutrophils facilitate this rupture, we used HL-60 cell line and found an enhanced collagenolytic activity, corresponding to matrix metalloproteinase 9 (MMP9), upon inflammatory stimuli. The immunohistochemical analyses revealed the accumulation of neutrophils around the site of rupture and the production of MMP9 from these cells in situ. Consistently, the collagenolytic activity of MMP9 could be detected in the lysate of ruptured lesions. These results suggest the crucial role of neutrophils to the rupture of intracranial aneurysms; implying neutrophils as a therapeutic or diagnostic target candidate.
other
2022-10-20 | A two-stage hybrid gene selection algorithm combined with machine learning models to predict the rupture status in intracranial aneurysms
An IA is an abnormal swelling of cerebral vessels, and a subset of these IAs can rupture causing aneurysmal subarachnoid hemorrhage (aSAH), often resulting in death or severe disability. Few studies have used an appropriate method of feature selection combined with machine learning by analyzing transcriptomic sequencing data to identify new molecular biomarkers. Following gene ontology (GO) and enrichment analysis, we found that the distinct status of IAs could lead to differential innate immune responses using all 913 differentially expressed genes, and considering that there are numerous irrelevant and redundant genes, we propose a mixed filter- and wrapper-based feature selection. First, we used the Fast Correlation-Based Filter (FCBF) algorithm to filter a large number of irrelevant and redundant genes in the raw dataset, and then used the wrapper feature selection method based on the he Multi-layer Perceptron (MLP) neural network and the Particle Swarm Optimization (PSO), accuracy (ACC) and mean square error (MSE) were then used as the evaluation criteria. Finally, we constructed a novel 10-gene signature (YIPF1, RAB32, WDR62, ANPEP, LRRCC1, AADAC, GZMK, WBP2NL, PBX1, and TOR1B) by the proposed two-stage hybrid algorithm FCBF-MLP-PSO and used different machine learning models to predict the rupture status in IAs. The highest ACC value increased from 0.817 to 0.919 (12.5% increase), the highest area under ROC curve (AUC) value increased from 0.87 to 0.94 (8.0% increase), and all evaluation metrics improved by approximately 10% after being processed by our proposed gene selection algorithm. Therefore, these 10 informative genes used to predict rupture status of IAs can be used as complements to imaging examinations in the clinic, meanwhile, this selected gene signature also provides new targets and approaches for the treatment of ruptured IAs.
2022-09-29 | An immunogenic cell death-related regulators classification patterns and immune microenvironment infiltration characterization in intracranial aneurysm based on machine learning
Immunogenic Cell Death (ICD) is a novel way to regulate cell death and can sufficiently activate adaptive immune responses. Its role in immunity is still emerging. However, the involvement of ICD in Intracranial Aneurysms (IA) remains unclear. This study aimed to identify biomarkers associated with ICDs and determine the relationship between them and the immune microenvironment during the onset and progression of IA.The IA gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in IA were identified and the effects of the ICD on immune microenvironment signatures were studied. Techniques like Lasso, Bayes, DT, FDA, GBM, NNET, RG, SVM, LR, and multivariate analysis were used to identify the ICD gene signatures in IA. A consensus clustering algorithm was used for conducting the unsupervised cluster analysis of the ICD patterns in IA. Furthermore, enrichment analysis was carried out for investigating the various immune responses and other functional pathways. Along with functional annotation, the weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network and module construction, identification of the hub gene, and co-expression analysis were also carried out.The above techniques were used for establishing the ICD gene signatures of HMGB1, HMGN1, IL33, BCL2, HSPA4, PANX1, TLR9, CLEC7A, and NLRP3 that could easily distinguish IA from normal samples. The unsupervised cluster analysis helped in identifying three ICD gene patterns in different datasets. Gene enrichment analysis revealed that the IA samples showed many differences in pathways such as the cytokine-cytokine receptor interaction, regulation of actin cytoskeleton, chemokine signaling pathway, NOD-like receptor signaling pathway, viral protein interaction with the cytokines and cytokine receptors, and a few other signaling pathways compared to normal samples. In addition, the three ICD modification modes showed obvious differences in their immune microenvironment and the biological function pathways. Eight ICD-regulators were identified and showed meaningful associations with IA, suggesting they could severe as potential prognostic biomarkers.A new gene signature for IA based on ICD features was created. This signature shows that the ICD pattern and the immune microenvironment are closely related to IA and provide a basis for optimizing risk monitoring, clinical decision-making, and developing novel treatment strategies for patients with IA.
2004-11-01 | Update on genetic evidence for rupture-prone compared with rupture-resistant intracranial saccular aneurysms
Object Anecdotal evidence exists for at least two subpopulations of intracranial saccular aneurysms; those that form rapidly and rupture when small and those that enlarge slowly and are particularly prone to rupture when they are 10 mm or more in diameter. The goal in this study was to determine if there was genetic evidence to support the classification of intracranial saccular aneurysms as “rupture-prone” or “rupture-resistant” lesions. Methods The authors prospectively obtained and analyzed clinical and genetic data in a cohort of 197 individuals composed of 58 patients with ruptured intracranial saccular aneurysms, 49 with unruptured aneurysms, and 90 healthy community volunteers. Based on recent studies supporting an increasingly relevant role for the critical vasomodulatory protein endothelial nitric oxide synthase (eNOS) in aneurysm pathobiology, the authors assayed blood from all 197 participants to determine and compare their eNOS genotypes. The eNOS gene intron 4 27–base pair variable-number tandem-repeat polymorphism was significantly overrepre-sented in persons with ruptured intracranial saccular aneurysms compared with community volunteers (p <0.002). When comparing eNOS genotypes among patients with ruptured or unruptured aneurysms, an approximately 10-fold increase in the odds of presenting with brain aneurysm rupture was found among individuals with multiple variant eNOS alleles (p = 0.004). Conclusions Uniquely, the authors have identified a set of eNOS gene variations whose presence indicates patients with intracranial saccular aneurysms that are more prone to rupture. The authors conclude that if these findings are reproducible in the setting of a large multicenter study, then in addition to known anatomical factors, a rapid and cost-effective genetic screening tool will become available to clinicians as an aid to predicting rupture risks in patients presenting with unruptured intracranial aneurysms.
cell therapies
2022-11-23 | Identification of The Unique Subtype of Macrophages in Aneurysm Lesions at the Growth Phase.
Recent experimental studies have defined intracranial aneurysms as a macrophage-mediated chronic inflammatory disease affecting intracranial arteries. Although there are various subtypes in macrophages, what type of macrophages is present in lesions during the disease development remains to be elucidated. The previously-established aneurysm model of rats was used. Macrophages were labeled with the fluorescent protein and isolated by a laser-microdissection method. The comprehensive gene expression profile analyses and gene ontology analyses was then done to identify a macrophage subtype present in lesions at the growth phase. The gene expression profile data of total 52 macrophages infiltrating into the lesions was acquired. The principal component analysis revealed the monotonous macrophage subtype. By comparing the profile identified with one from in vitro-differentiated M0 or M1 macrophages, the macrophages in the lesions were belonged to the simple and unique subtype. Because the perception of signaling from nervous system was highlighted as up-represented terms through gene ontology analyses, the macrophage subtype in lesions at the growth phase might be differentiated under the influence of nervous system in the microenvironment. The histopathological examinations supported the above notion by confirming the presence of nerves in the adventitia. The findings from the present study have provided the useful insights about the macrophage subtype in aneurysm lesions at the growth phase and also proposed its ability as a therapeutic target.
2022-10-01 | Dental Pulp Stem Cell-Derived Conditioned Medium Alleviates Subarachnoid Hemorrhage-Induced Microcirculation Impairment by Promoting M2 Microglia Polarization and Reducing Astrocyte Swelling
Aneurysmal subarachnoid hemorrhage (SAH) can cause severe neurological deficits and high mortality. Early brain edema following SAH contributes to the initiation of microcirculation impairment and may further lead to delayed ischemic neurologic deficit (DIND). This study aimed to investigate whether dental pulp stem cell conditioned medium (DPSC-CM) ameliorates SAH-induced microcirculation impairment and the underlying mechanisms. SAH was induced via intrathecal injection of fresh autologous blood in Wistar male adult rat. DPSC-CM or DPSC-CM + insulin growth factor-1 (IGF-1) antibody was randomly administered by intrathecal route 5 min after SAH induction. To evaluate the underlying mechanisms of DPSC-CM in the treatment of SAH, primary rat astrocyte and microglia co-cultures were challenged with hemolysate or SAH-patient CSF in the presence or absence of DPSC-CM. The results showed that in vivo, DPSC-CM treatment decreased the brain water content, improved microcirculation impairment and enhanced functional recovery at 24 h post-SAH. DPSC-CM treatment also alleviated the expressions of water channel protein aquaporin-4 (AQP4) and pro-inflammatory cytokines, and enhanced the expressions of anti-inflammatory factors in the cortical region. However, all the beneficial effects of DPSC-CM were abrogated after treatment with IGF-1 neutralizing antibody. The in vitro results further showed that DPSC-CM treatment reduced hemolysate/SAH-patient CSF-induced astrocyte swelling and promoted M2 microglia polarization, partially through IGF-1/AKT signaling. The data suggested that DPSC-CM significantly reduced brain edema and rescued microcirculation impairment with concomitant anti-inflammatory benefits after SAH, and may potentially be developed into a novel therapeutic strategy for SAH.
2018-07-07 | Endothelial Cell Dysfunction and Injury in Subarachnoid Hemorrhage
In the brain, vascular endothelial cells conserve blood viscosity, control blood flow, and form the interface between central nervous system and circulating blood. Clinical outcome after aneurysmal subarachnoid hemorrhage is linked to early brain injury, cerebral vasospasm, and other causes of delayed cerebral ischemia. The cerebral vasculature remains a unique target for therapies since it becomes rapidly disrupted after subarachnoid hemorrhage, and damage to the blood vessels continues into the delayed injury phase. The current failure of therapies to improve clinical outcome warrants a re-evaluation of current therapeutic approaches. The mechanisms of endothelial cell injury and blood–brain barrier breakdown are critical to the pathway of cerebral injury, and an improved understanding of these mechanisms may lead to novel therapeutic targets. This review provides an update on the current understanding of endothelial cell injury following aneurysmal subarachnoid hemorrhage, including blood–brain barrier dysfunction.
2014-02-28 | Therapeutic Benefit of Bone Marrow–Derived Endothelial Progenitor Cell Transplantation after Experimental Aneurysm Embolization with Coil in Rats
Aneurysm embolization with coil is now widely used clinically. However, the recurrence of aneurysms after embolization has always plagued neurosurgeons because the endothelial layer of the aneurysm neck loses its integrity after being embolized by coil. Bone marrow–derived endothelial progenitor cells (BM-EPCs) could be incorporated into injured endothelium and differentiate into mature endothelial cells during vascular repairing processes. The aim of our study is to explore the effects of BM-EPCs on aneurysm repairing and remodeling in a rat embolization model of abdominal aortic aneurysm. BM-EPC proliferation, migration and tube formation were not affected by super-paramagnetic iron oxide nanoparticle (SPIO) labeling compared to the controls (p>0.05). The number of SPIO-labeled cells greatly increased in EPC transplanted rats compared to that of phosphate buffered saline treated rats. SPIO-labeled EPC (SPIO-EPC) are mainly located in the aneurysm neck and surrounded by fibrous tissue. A histology study showed that the aneurysm orifice was closed with neointima and the aneurysm was filled with newly formed fibrous tissue. The SPIO-EPC accumulated in the aneurysm neck, which accelerated focal fibrous tissue remodeling, suggesting that BM-EPCs play a crucial role in repairing and remodeling the aneurysm neck orifice.
1996-09-01 | Management of Nontraumatic Subarachnoid Hemorrhage in a Patient with Sickle‐cell Disease: A Case Report
Subarachnoid hemorrhage (SAH) due to sickle-cell anemia is rare, but potentially devastating. However, with early recognition of SAH, aggressive support with exchange transfusion, cerebral angiography, and neurosurgical intervention, a positive outcome may be achieved. A case report of SAH managed in this fashion is reported. Based on similar cases in the literature, a suggested treatment protocol is provided for the management of nontraumatic SAH in sickle-cell patients presenting to the ED.
antibodies
2024-05-23 | Modulation of the Immunological Milieu in Acute Aneurysmal Subarachnoid Hemorrhage: The Potential Role of Monocytes Through CXCL10 Secretion.
Emerging evidence indicates that aneurysmal subarachnoid hemorrhage (aSAH) elicits a response from both innate and adaptive immune systems. An upregulation of CD8 + CD161 + cells has been observed in the cerebrospinal fluid (CSF) after aSAH, yet the precise role of these cells in the context of aSAH is unkown. CSF samples from patients with aSAH and non-aneurysmal SAH (naSAH) were analyzed. Single-cell RNA sequencing (scRNAseq) was performed on CD8 + CD161 + sorted samples from aSAH patients. Cell populations were identified using "clustering." Gene expression levels of ten previously described genes involved in inflammation were quantified from aSAH and naSAH samples using RT-qPCR. The study focused on the following genes: CCL5, CCL7, APOE, SPP1, CXCL8, CXCL10, HMOX1, LTB, MAL, and HLA-DRB1. Gene clustering analysis revealed that monocytes, NK cells, and T cells expressed CD8 + CD161 + in the CSF of patients with aSAH. In comparison to naSAH samples, aSAH samples exhibited higher mRNA levels of CXCL10 (median, IQR = 90, 16-149 vs. 0.5, 0-6.75, p = 0.02). A trend towards higher HMOX1 levels was also observed in aSAH (median, IQR = 12.6, 9-17.6 vs. 2.55, 1.68-5.7, p = 0.076). Specifically, CXCL10 and HMOX1 were expressed by the monocyte subpopulation. Monocytes, NK cells, and T cells can potentially express CD8 + CD161 + in patients with aSAH. Notably, monocytes show high levels of CXCL10. The elevated expression of CXCL10 in aSAH compared to naSAH indicates its potential significance as a target for future studies.
2024-04-04 | The Role of Tnf and Soluble Tnf Receptors (TNFR1/2) as Therapeutic Targets for Inflammation Secondary to Intracerebral Stroke and Hemorrhage
Most neurodegenerative diseases, including Alzheimer's disease, ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage are associated with inflammation. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine that regulates cerebral infarction in stroke pathology, and its action is influenced by the bioavailability of its membrane-bound receptors, TNFR1 and TNFR2, and microglial activation. During the initial onset of these diseases, the soluble variant of the cytokine presents with prolonged and excessive activation of TNFR1, resulting in cell death and long-term neurological impairments. Therapeutic interventions for neurodegenerative diseases have targeted TNF to limit the onset of neuroinflammation. First-generation therapeutics have been demonstrated to inhibit membrane-bound TNF to TNFR2 receptor binding, resulting in severe side effects such as infections and cancer. As such, second-generation drugs, including XPro1595, have been developed to selectively inhibit soluble TNF and impede the effects of TNFR1 while still allowing for TNFR2 activation. Early results in murine TBI models demonstrate reduced glial reactivity by 50%, reduced dendritic degeneration by 30%, increased plasticity by 15%, and improved functional outcomes by 20% post-TBI. This scoping review of TNF receptors in various neurodegenerative diseases seeks to evaluate current and future therapeutic strategies as well as highlight potential strategies to eliminate confounding variables present in the current literature.
2023-05-21 | Single‐Cell RNA Sequencing and Spatial Transcriptomics Reveal Pathogenesis of Meningeal Lymphatic Dysfunction after Experimental Subarachnoid Hemorrhage
Abstract Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke with high mortality and disability rate. Meningeal lymphatic vessels (mLVs) are a newly discovered intracranial fluid transport system and are proven to drain extravasated erythrocytes from cerebrospinal fluid into deep cervical lymph nodes after SAH. However, many studies have reported that the structure and function of mLVs are injured in several central nervous system diseases. Whether SAH can cause mLVs injury and the underlying mechanism remain unclear. Herein, single‐cell RNA sequencing and spatial transcriptomics are applied, along with in vivo / vitro experiments, to investigate the alteration of the cellular, molecular, and spatial pattern of mLVs after SAH. First, it is demonstrated that SAH induces mLVs impairment. Then, through bioinformatic analysis of sequencing data, it is discovered that thrombospondin 1 (THBS1) and S100A6 are strongly associated with SAH outcome. Furthermore, the THBS1‐CD47 ligand‐receptor pair is found to function as a key role in meningeal lymphatic endothelial cell apoptosis via regulating STAT3/Bcl‐2 signaling. The results illustrate a landscape of injured mLVs after SAH for the first time and provide a potential therapeutic strategy for SAH based on mLVs protection by disrupting THBS1 and CD47 interaction.
2019-12-01 | Innate immunity activation in the early brain injury period following subarachnoid hemorrhage
Aneurysmal subarachnoid hemorrhage (SAH) is a catastrophic disease with devastating consequences, including a high mortality rate and severe disabilities among survivors. Inflammation is induced following SAH, but the exact role and phenotype of innate immune cells remain poorly characterized. We investigated the inflammatory components of the early brain injury in an animal model and in SAH patients.SAH was induced through injection of blood in the subarachnoid space of C57Bl/6 J wild-type mice. Prospective blood collections were obtained at 12 h, days 1, 2, and 7 to evaluate the systemic inflammatory consequences of SAH by flow cytometry and enzyme-linked immunosorbent-assay (ELISA). Brains were collected, enzymatically digested, or fixed to characterize infiltrating inflammatory cells and neuronal death using flow cytometry and immunofluorescence. Phenotypic evaluation was performed at day 7 using the holding time and footprint tests. We then compared the identified inflammatory proteins to the profiles obtained from the plasma of 13 human SAH patients.Following SAH, systemic IL-6 levels increased rapidly, whereas IL-10 levels were reduced. Neutrophils were increased both in the brain and in the blood reflecting local and peripheral inflammation following SAH. More intracerebral pro-inflammatory monocytes were found at early time points. Astrocyte and microglia activation were also increased, and mice had severe motor deficits, which were associated with an increase in the percentage of caspase-3-positive apoptotic neurons. Similarly, we found that IL-6 levels in patients were rapidly increased following SAH. ICAM-1, bFGF, IL-7, IL-12p40, and MCP-4 variations over time were different between SAH patients with good versus bad outcomes. Moreover, high levels of Flt-1 and VEGF at admission were associated with worse outcomes.SAH induces an early intracerebral infiltration and peripheral activation of innate immune cells. Furthermore, microglia and astrocytic activation are present at later time points. Our human and mouse data illustrate that SAH is a systemic inflammatory disease and that immune cells represent potential therapeutic targets to help this population of patients in need of new treatments.
2018-11-30 | Inflammatory Smooth Muscle Cells Induce Endothelial Cell Alterations to Influence Cerebral Aneurysm Progression via Regulation of Integrin and VEGF Expression
Cerebral aneurysm growth is characterized by vessel wall frailness, although the underlying cellular mechanisms are unclear. Here, we examined the relationship between inflammatory smooth muscle cells (SMCs) and endothelial cells (ECs) in cerebral aneurysms, including the mechanisms underlying inflammatory SMC-induced changes in ECs. Five saccular cerebral aneurysms were collected and five temporal artery samples were used as controls. Cells and cytokines were detected by immunohistochemistry and TUNEL (transferase dUTP nick end labeling) assays performed to evaluate apoptosis. Human umbilical vein endothelial cells (HUVECs) were seeded on collagen I, IV, and VI-coated plates for cell adhesion assays and inflammatory SMCs (iSMCs) were established by culture in flexible silicone chambers subjected to cyclic mechanical stretch. HUVECs were cultured in iSMC-conditioned medium, followed by evaluation of their viability, apoptosis, and function, and determination of VEGF (vascular endothelial growth factor) -A and integrin levels by western blotting. Aneurysm tissue contained fewer SMCs and lacked ECs. In aneurysm walls, more matrix metalloproteinase (MMP) -1, MMP-3, and apoptotic cells were detected, accompanied by decreased collagen IV and VI levels. Cell adhesion assays revealed that more HUVECs were attached in collagen IV and VI-coated plates compared with controls. iSMC-conditioned medium significantly reduced HUVEC viability and apoptosis showed an increased trend; however, the difference was not significant. iSMC medium also reduced tube formation and migration of HUVECs. Moreover, iSMC medium reduced HUVEC expression of VEGF-A, integrin α1, integrin α2, and integrin β. Our data demonstrate a lack of SMCs and ECs in aneurysm walls, accompanied by elevated MMP and decreased collagen levels. In vitro assays showed that iSMCs induced reduction in EC adhesion, and caused EC dysfunction. Understanding of the relationships among SMC, EC, and collagens during aneurysm progression provides an additional therapeutic option for prevention of cerebral aneurysm progression.
small molecules
2024-06-11 | Oxygen-based autoregulation indices associated with clinical outcomes and spreading depolarization in aSAH
Background Impairment in cerebral autoregulation has been proposed as a potentially targetable factor in patients with aneurysmal subarachnoid hemorrhage (aSAH), however there are different continuous measures that can be used to calculate the state of autoregulation. In addition, it has previously been proposed that there may be an association of impaired autoregulation with the occurrence of spreading depolarization (SD) events. Methods Subjects with invasive multimodal monitoring and aSAH were enrolled in an observational study. Autoregulation indices were prospectively calculated from this database as a 10 second moving correlation coefficient between various cerebral blood flow (CBF) surrogates and mean arterial pressure (MAP). In subjects with subdural ECoG (electrocorticography) monitoring, SD was also scored. Associations between clinical outcomes using the mRS (modified Rankin Scale) and occurrence of either isolated or clustered SD was assessed. Results 320 subjects were included, 47 of whom also had ECoG SD monitoring. As expected, baseline severity factors such as mFS and WFNS (World Federation of Neurosurgical Societies scale) were strongly associated with the clinical outcome. SD probability was related to blood pressure in a triphasic pattern with a linear increase in probability below MAP of ~ 100mmHg. Autoregulation indices were available for intracranial pressure (ICP) measurements (PRx), PbtO2 from Licox (ORx), perfusion from the Bowman perfusion probe (CBFRx), and cerebral oxygen saturation measured by near infrared spectroscopy (OSRx). Only worse ORx and OSRx were associated with worse clinical outcomes. ORx and OSRx also were found to both increase in the hour prior to SD for both sporadic and clustered SD. Conclusions Impairment in autoregulation in aSAH is associated with worse clinical outcomes and occurrence of SD when using ORx and OSRx. Impaired autoregulation precedes SD occurrence. Targeting the optimal MAP or cerebral perfusion pressure in patients with aSAH should use ORx and/or OSRx as the input function rather than intracranial pressure.
2024-04-14 | Taurine ameliorates sensorimotor function by inhibiting apoptosis and activating A2 astrocytes in mice after subarachnoid hemorrhage
Abstract Subarachnoid hemorrhage (SAH) is a form of severe acute stroke with very high mortality and disability rates. Early brain injury (EBI) and delayed cerebral ischemia (DCI) contribute to the poor prognosis of patients with SAH. Currently, some researchers have started to focus on changes in amino acid metabolism that occur in brain tissues after SAH. Taurine is a sulfur-containing amino acid that is semi-essential in animals, and it plays important roles in various processes, such as neurodevelopment, osmotic pressure regulation, and membrane stabilization. In acute stroke, such as cerebral hemorrhage, taurine plays a neuroprotective role. However, the role of taurine after subarachnoid hemorrhage has rarely been reported. In the present study, we established a mouse model of SAH. We found that taurine administration effectively improved the sensorimotor function of these mice. In addition, taurine treatment alleviated sensorimotor neuron damage and reduced the proportion of apoptotic cells. Furthermore, taurine treatment enhanced the polarization of astrocytes toward the neuroprotective phenotype while inhibiting their polarization toward the neurotoxic phenotype. This study is the first to reveal the relationship between taurine and astrocyte polarization and may provide a new strategy for SAH research and clinical treatment.
2024-03-19 | The Role of Epigenetics in Brain Aneurysm and Subarachnoid Hemorrhage: A Comprehensive Review
This comprehensive review explores the emerging field of epigenetics in intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (aSAH). Despite recent advancements, the high mortality of aSAH needs an understanding of its underlying pathophysiology, where epigenetics plays a crucial role. This review synthesizes the current knowledge, focusing on three primary epigenetic mechanisms: DNA methylation, non-coding RNA (ncRNA), and histone modification in IA and aSAH. While DNA methylation studies are relatively limited, they suggest a significant role in the pathogenesis and prognosis of IA and aSAH, highlighting differentially methylated positions in genes presumably involved in these pathologies. However, methodological limitations, including small sample sizes and a lack of diverse population studies, temper these results. The role of ncRNAs, particularly miRNAs, has been more extensively studied, but there are still few studies focused on histone modifications. Despite methodological challenges and inconsistent findings, these studies underscore the involvement of miRNAs in key pathophysiological processes, including vascular smooth muscle regulation and the inflammatory response. This review emphasizes methodological challenges in epigenetic research, advocating for large-scale epigenome-wide association studies integrating genetic and environmental factors, along with longitudinal studies. Such research could unravel the complex mechanisms behind IA and aSAH, guiding the development of targeted therapeutic approaches.
2024-03-13 | Neuroradiological diagnosis and therapy of cerebral vasospasm after subarachnoid hemorrhage
Background Cerebral damage after aneurysmal subarachnoid hemorrhage (SAH) results from various, sometimes unrelated causes. After the initial hemorrhage trauma with an increase in intracranial pressure, induced vasoconstriction, but also microcirculatory disturbances, inflammation and pathological electrophysiological processes (cortical spreading depolarization) can occur in the course of the disease, resulting in delayed cerebral ischemia (DCI). In the neuroradiological context, cerebral vasospasm (CVS) remains the focus of diagnostic imaging and endovascular therapy as a frequent component of the genesis of DCI. Methods The amount of blood leaked during aneurysm rupture (which can be detected by CT, for example) correlates with the occurrence and severity of CVS. CT perfusion is then an important component in determining the indication for endovascular spasm therapies (EST). These include intra-arterial drug administration (also as long-term microcatheter treatment) and mechanical procedures (balloon angioplasty, vasodilatation using other instruments such as stent retrievers, stenting). Conclusion This review summarizes the current findings on the diagnosis and treatment of CVS after aneurysmal SAH from a neuroradiological perspective, taking into account the complex and up-to-date international literature. Key Points Citation Format
2024-01-30 | Endovascular complications: Antiplatelet management for flow diversion
Up to 3−5% of the general population is affected by cerebral aneurysms that are associated with both modifiable as well as non-modifiable risk factors ranging from familial to acquired neurovascular conditions. The initial treatment option was aneurysm clipping and evolved to including primary or adjuvant endovascular treatment. Aneurysm re-rupture, although rare, can have devastating consequences such as intracranial bleeding and carotidcavernous fistula. Emergent surgery in view of delayed aneurysm rupture in patients maintained on dual antiplatelet therapy presents with the need to carefully assess the procedure-related risk factors and evaluate the patients’ platelet function. With the advent of novel technology, flow diverters came into play. These devices utilize the deployment of metallic stents into the parent artery that serves the diversion of blood flow away from the pouching aneurysm. Despite their efficacy, flow diverter insertion and catheter manipulation come with a risk of developing ischemia and stroke, hemorrhage and aneurysm re-rupture, in-stent thrombosis and stenosis, and aneurysmal occlusion amongst other complications. The prospect of thromboembolic events necessitates the use of aggressive antiplatelet regimen with the dual antiplatelet regimen utilizing clopidogrel and aspirin used most frequently. Prasugrel and Ticagrelor have been shown to be superior to Clopidogrel in terms of thromboembolic consequences in cardiovascular literature. Given their potential benefit over the current standard of treatment in this patient population, more extensive randomized-controlled studies are warranted for the evaluation of the efficacy and non-inferiority of Prasugrel and Aspirin or Ticagrelor and Aspirin to Clopidogrel and Aspirin.
proteins
2024-11-28 | Multi-targeted olink proteomics analyses of cerebrospinal fluid from patients with aneurysmal subarachnoid hemorrhage.
The complexity of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) may require the simultaneous analysis of variant types of protein biomarkers to describe it more accurately. In this study, we analyzed for the first time the alterations of cerebrospinal fluid (CSF) proteins in patients with aSAH by multi-targeted Olink proteomics, aiming to reveal the pathophysiology of DCI and provide insights into the diagnosis and treatment of aSAH. Six aSAH patients and six control patients were selected, and CSF samples were analyzed by Olink Proteomics (including 96-neurology panel and 96-inflammation panel) based on Proximity Extension Assay (PEA). Differentially expressed proteins (DEPs) were acquired and bioinformatics analysis was performed. PCA analysis revealed better intra- and inter-group reproducibility of CSF samples in the control and aSAH groups. 23 neurology-related and 31 inflammation-relevant differential proteins were identified. In the neurology panel, compared to controls, the up-regulated proteins in the CSF of SAH patients predominantly included macrophage scavenger receptor 1 (MSR1), siglec-1, siglec-9, cathepsin C (CTSC), cathepsin S (CTSS), etc. Meanwhile, in the inflammation group, the incremental proteins mainly contained interleukin-6 (IL-6), MCP-1, CXCL10, CXCL-9, TRAIL, etc. Cluster analysis exhibited significant differences in differential proteins between the two groups. GO function enrichment analysis hinted that the differential proteins pertinent to neurology in the CSF of SAH patients were mainly involved in the regulation of defense response, vesicle-mediated transport and regulation of immune response; while the differential proteins related to inflammation were largely connected with the cellular response to chemokine, response to chemokine and chemokine-mediated signaling pathway. Additionally, in the neurology panel, KEGG enrichment analysis indicated that the differential proteins were significantly enriched in the phagosome, apoptosis and microRNAs in cancer pathway. And in the inflammation panel, the differential proteins were mainly enriched in the chemokine signaling pathway, viral protein interaction with cytokine and cytokine receptor and toll-like receptor signaling pathway. These identified differential proteins reveal unique pathophysiological characteristics secondary to aSAH. Further characterization of these proteins and aberrant pathways in future research could enable their application as potential therapeutic targets and biomarkers for DCI after aSAH.
2023-07-13 | Circulating Inflammatory Biomarkers and Risk of Intracranial Aneurysm: A Mendelian Randomization Study
Abstract Background Intracranial aneurysm (IA) accounts for a substantial source of non-traumatic subarachnoid hemorrhage, with inflammation postulated as a potential factor in its pathogenesis. The present study aims at evaluating the association between circulating inflammatory cytokines and risk of IA under a bidirectional two-sample Mendelian randomization (MR) design. Methods For primary analysis, summary statistics of inflammatory regulators was obtained from a genome-wide association study (GWAS) comprising 8,293 Finnish participants. Summary data of IA was extracted from a GWAS which comprised 7,495 cases and 71,934 controls in European descent. For targeted analysis, summary statistics were extracted from two proteomic studies, which recruit 3,301 and 5,368 European participants, respectively. Summary data of IA were acquired from FinnGen study with 5,342 cases and 342,673 controls. We employed inverse variance weighted (IVW) method as main approach, with sensitivity analyses using weighted median, MR-Egger, and MR-PRESSO methods. Reverse MR analyses were conducted to minimize bias from reverse causality. Results No causation of cytokines with IA was identified in both primary and targeted analysis after Bonferroni correction. In primary analysis, vascular endothelial growth factor (VEGF) and fibroblast growth factor basic (bFGF) levels were suggestively associated with IA [(VEGF→IA: odds ratio (OR) = 1.11, 95% confidence interval (95% CI) = 1.02–1.20, P = 0.01; bFGF→IA: OR = 0.68, 95% CI = 0.48–0.96, P = 0.03]. Statistical significance failed to replicate in targeted analysis. Instead, suggestive protective effects for aneurysmal subarachnoid hemorrhage (aSAH) were identified in FGF-9 (FGF-9→aSAH: OR = 0.74, 95% CI = 0.62–0.89, P = 0.001) and FGF-16 (FGF-16→aSAH: OR = 0.84, 95% CI = 0.72–0.97, P = 0.017). Furthermore, reverse analyses identified suggestive effect of IA and its subtypes on IL-10, RANTES, MIF, GRO-alpha, FGF-16, and FGF-19. Result remained robust after applying sensitivity tests. Conclusions Our study provided novel insights into the potential protective role of FGF-9 and FGF-16 in aSAH. Future studies are in need to evaluate the temporal dynamics of cytokines in conjunction with IA.
2023-03-27 | Narrative review of roles of astrocytes in subarachnoid hemorrhage
Background and Objective: Astrocytes play an important role in healthy brain function, including the development and maintenance of blood-brain barrier (BBB), structural support, brain homeostasis, neurovascular coupling and secretion of neuroprotective factors.Reactive astrocytes participate in various pathophysiology after subarachnoid hemorrhage (SAH) including neuroinflammation, glutamate toxicity, brain edema, vasospasm, BBB disruption, cortical spreading depolarization (SD).Methods: We searched PubMed up to 31 May, 2022 and evaluated the articles for screening and inclusion for subsequent systemic review.We found 198 articles with the searched terms.After exclusion based on the selection criteria, we selected 30 articles to start the systemic review. Key Content and Findings:We summarized the response of astrocytes induced by SAH.Astrocytes are critical for brain edema formation, BBB reconstruction and neuroprotection in the acute stage of SAH.Astrocytes clear extracellular glutamate by increasing the uptake of glutamate and Na + /K + ATPase activity after SAH.Neurotrophic factors released by astrocytes contribute to neurological recovery after SAH.Meanwhile, Astrocytes also form glial scars which hinder axon regeneration, produce proinflammatory cytokines, free radicals, and neurotoxic molecules.Conclusions: Preclinical studies showed that therapeutic targeting the astrocytes response could have a beneficial effect in ameliorating neuronal injury and cognitive impairment after SAH.Clinical trials and preclinical animal studies are still urgently needed in order to determine where astrocytes stand in various pathway of brain damage and repair after SAH and, above all, to develop therapeutic approaches which benefit patient outcomes.
2021-02-09 | ANGPTL6 Genetic Variants Are an Underlying Cause of Familial Intracranial Aneurysms.
To understand the role of the angiopoietin-like 6 gene (ANGPTL6) in intracranial aneurysms (IAs), we investigated its role in a large cohort of familial IAs.Individuals with family history of IA were recruited to the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study. The ANGPTL6 gene was sequenced using Sanger sequencing. Identified genetic variants were compared to a control population.We found 6 rare ANGPTL6 genetic variants in 9/275 individuals with a family history of IA (3.3%) (5 missense mutations and 1 nonsense mutation leading to a premature stop codon), none present in controls. One of these had been previously reported: c.392A>T (p.Glu131Val) on exon 2; another was very close: c.332G>A (p.Arg111His). Two further genetic variants lie within the fibrinogen-like domain of the ANGPTL6 gene, which may influence function or level of the ANGPTL6 protein. The last 2 missense mutations lie within the coiled-coil domain of the ANGPTL6 protein. All genetic variants were well conserved across species.ANGPTL6 genetic variants are an important cause of IA. Defective or lack of ANGPTL6 protein is therefore an important factor in blood vessel proliferation leading to IA; dysfunction of this protein is likely to cause abnormal proliferation or weakness of vessel walls. With these data, not only do we emphasize the importance of screening familial IA cases for ANGPTL6 and other genes involved in IA, but also highlight the ANGPTL6 pathway as a potential therapeutic target.This is a Class III study showing some specificity of presence of the ANGPTL6 gene variant as a marker of familial intracranial aneurysms in a small subset of individuals with familial aneurysms.
2020-11-17 | Involvement of neutrophils in machineries underlying the rupture of intracranial aneurysms in rats
Subarachnoid hemorrhage due to rupture of an intracranial aneurysm has a quite poor prognosis after the onset of symptoms, despite the modern technical advances. Thus, the mechanisms underlying the rupture of lesions should be clarified. To this end, we obtained gene expression profile data and identified the neutrophil-related enriched terms in rupture-prone lesions using Gene Ontology analysis. Next, to validate the role of neutrophils in the rupture of lesions, granulocyte-colony stimulating factor (G-CSF) was administered to a rat model, in which more than half of induced lesions spontaneously ruptured, leading to subarachnoid hemorrhage. As a result, G-CSF treatment not only increased the number of infiltrating neutrophils, but also significantly facilitated the rupture of lesions. To clarify the mechanisms of how neutrophils facilitate this rupture, we used HL-60 cell line and found an enhanced collagenolytic activity, corresponding to matrix metalloproteinase 9 (MMP9), upon inflammatory stimuli. The immunohistochemical analyses revealed the accumulation of neutrophils around the site of rupture and the production of MMP9 from these cells in situ. Consistently, the collagenolytic activity of MMP9 could be detected in the lysate of ruptured lesions. These results suggest the crucial role of neutrophils to the rupture of intracranial aneurysms; implying neutrophils as a therapeutic or diagnostic target candidate.
other
2022-10-20 | A two-stage hybrid gene selection algorithm combined with machine learning models to predict the rupture status in intracranial aneurysms
An IA is an abnormal swelling of cerebral vessels, and a subset of these IAs can rupture causing aneurysmal subarachnoid hemorrhage (aSAH), often resulting in death or severe disability. Few studies have used an appropriate method of feature selection combined with machine learning by analyzing transcriptomic sequencing data to identify new molecular biomarkers. Following gene ontology (GO) and enrichment analysis, we found that the distinct status of IAs could lead to differential innate immune responses using all 913 differentially expressed genes, and considering that there are numerous irrelevant and redundant genes, we propose a mixed filter- and wrapper-based feature selection. First, we used the Fast Correlation-Based Filter (FCBF) algorithm to filter a large number of irrelevant and redundant genes in the raw dataset, and then used the wrapper feature selection method based on the he Multi-layer Perceptron (MLP) neural network and the Particle Swarm Optimization (PSO), accuracy (ACC) and mean square error (MSE) were then used as the evaluation criteria. Finally, we constructed a novel 10-gene signature (YIPF1, RAB32, WDR62, ANPEP, LRRCC1, AADAC, GZMK, WBP2NL, PBX1, and TOR1B) by the proposed two-stage hybrid algorithm FCBF-MLP-PSO and used different machine learning models to predict the rupture status in IAs. The highest ACC value increased from 0.817 to 0.919 (12.5% increase), the highest area under ROC curve (AUC) value increased from 0.87 to 0.94 (8.0% increase), and all evaluation metrics improved by approximately 10% after being processed by our proposed gene selection algorithm. Therefore, these 10 informative genes used to predict rupture status of IAs can be used as complements to imaging examinations in the clinic, meanwhile, this selected gene signature also provides new targets and approaches for the treatment of ruptured IAs.
2022-09-29 | An immunogenic cell death-related regulators classification patterns and immune microenvironment infiltration characterization in intracranial aneurysm based on machine learning
Immunogenic Cell Death (ICD) is a novel way to regulate cell death and can sufficiently activate adaptive immune responses. Its role in immunity is still emerging. However, the involvement of ICD in Intracranial Aneurysms (IA) remains unclear. This study aimed to identify biomarkers associated with ICDs and determine the relationship between them and the immune microenvironment during the onset and progression of IA.The IA gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in IA were identified and the effects of the ICD on immune microenvironment signatures were studied. Techniques like Lasso, Bayes, DT, FDA, GBM, NNET, RG, SVM, LR, and multivariate analysis were used to identify the ICD gene signatures in IA. A consensus clustering algorithm was used for conducting the unsupervised cluster analysis of the ICD patterns in IA. Furthermore, enrichment analysis was carried out for investigating the various immune responses and other functional pathways. Along with functional annotation, the weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network and module construction, identification of the hub gene, and co-expression analysis were also carried out.The above techniques were used for establishing the ICD gene signatures of HMGB1, HMGN1, IL33, BCL2, HSPA4, PANX1, TLR9, CLEC7A, and NLRP3 that could easily distinguish IA from normal samples. The unsupervised cluster analysis helped in identifying three ICD gene patterns in different datasets. Gene enrichment analysis revealed that the IA samples showed many differences in pathways such as the cytokine-cytokine receptor interaction, regulation of actin cytoskeleton, chemokine signaling pathway, NOD-like receptor signaling pathway, viral protein interaction with the cytokines and cytokine receptors, and a few other signaling pathways compared to normal samples. In addition, the three ICD modification modes showed obvious differences in their immune microenvironment and the biological function pathways. Eight ICD-regulators were identified and showed meaningful associations with IA, suggesting they could severe as potential prognostic biomarkers.A new gene signature for IA based on ICD features was created. This signature shows that the ICD pattern and the immune microenvironment are closely related to IA and provide a basis for optimizing risk monitoring, clinical decision-making, and developing novel treatment strategies for patients with IA.
2004-11-01 | Update on genetic evidence for rupture-prone compared with rupture-resistant intracranial saccular aneurysms
Object Anecdotal evidence exists for at least two subpopulations of intracranial saccular aneurysms; those that form rapidly and rupture when small and those that enlarge slowly and are particularly prone to rupture when they are 10 mm or more in diameter. The goal in this study was to determine if there was genetic evidence to support the classification of intracranial saccular aneurysms as “rupture-prone” or “rupture-resistant” lesions. Methods The authors prospectively obtained and analyzed clinical and genetic data in a cohort of 197 individuals composed of 58 patients with ruptured intracranial saccular aneurysms, 49 with unruptured aneurysms, and 90 healthy community volunteers. Based on recent studies supporting an increasingly relevant role for the critical vasomodulatory protein endothelial nitric oxide synthase (eNOS) in aneurysm pathobiology, the authors assayed blood from all 197 participants to determine and compare their eNOS genotypes. The eNOS gene intron 4 27–base pair variable-number tandem-repeat polymorphism was significantly overrepre-sented in persons with ruptured intracranial saccular aneurysms compared with community volunteers (p <0.002). When comparing eNOS genotypes among patients with ruptured or unruptured aneurysms, an approximately 10-fold increase in the odds of presenting with brain aneurysm rupture was found among individuals with multiple variant eNOS alleles (p = 0.004). Conclusions Uniquely, the authors have identified a set of eNOS gene variations whose presence indicates patients with intracranial saccular aneurysms that are more prone to rupture. The authors conclude that if these findings are reproducible in the setting of a large multicenter study, then in addition to known anatomical factors, a rapid and cost-effective genetic screening tool will become available to clinicians as an aid to predicting rupture risks in patients presenting with unruptured intracranial aneurysms.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
23 orphan drug designations for Acquired aneurysmal subarachnoid hemorrhage, including 1 approved therapy.
23 orphan drug designations for Acquired aneurysmal subarachnoid hemorrhage, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Ixodes ricinus contact phase inhibitor | — | EMA | 2025-03-25 | — | Bioxodes |
ceriopolymex | other | FDA | 2024-12-26 | — | Cenyx Biotech Inc. |
nimodipine intravenous | small molecules | FDA | 2023-08-01 | — | Cipla Ltd. |
haptoglobin (Hp1-1), (Human) | proteins | FDA | 2021-10-12 | — | CSL Behring |
(R)-6-(2-hydroxy-3-(4-(4-(trifluoromethyl)phenyl)piperazin- 1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one | small molecules | FDA | 2020-11-17 | — | NeurOp Inc. |
Lumacaftor | small molecules | FDA | 2020-09-09 | — | Qanatpharma AG |
Fasudil hydrochloride | small molecules | EMA | 2020-07-27 | — | Aneuryst (Ireland) Limited |
Lumacaftor | small molecules | EMA | 2020-06-04 | — | Prof. Dr Steffen-Sebastian Bolz |
Nicardipine | small molecules | EMA | 2020-01-09 | — | Bit Pharma GmbH |
fasudil | small molecules | FDA | 2019-09-05 | — | Aneuryst, Inc. |
melatonin | small molecules | FDA | 2018-03-28 | — | WORPHMED Srl |
1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene | small molecules | EMA | 2017-11-08 | — | Edvince AB |
nimodipine intravenous | small molecules | FDA | 2017-08-10 | — | Grace Therapeutics U.S., Inc. |
1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene | small molecules | FDA | 2017-08-03 | — | Edvince AB |
stabilized sulforaphane | small molecules | FDA | 2016-08-22 | — | Evgen Pharma PLC |
glyburide | small molecules | FDA | 2016-02-08 | — | Remedy Pharmaceuticals, Inc. |
Nimodipine | small molecules | EMA | 2015-10-09 | — | Granzer Regulatory Consulting & Services GmbH |
intraventricular nimodipine | small molecules | FDA | 2015-05-28 | — | Edge Therapeutics, Inc. |
Sodium nitrite | small molecules | EMA | 2014-01-16 | — | Hope Pharmaceuticals Limited |
H-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-alys-aleu-Ser-Ser-Ile-Glu-Ser-Asp-Val-OH | peptides | FDA | 2013-05-14 | — | NoNO, Inc. |
nimodipine [NYMALIZE] | small molecules | FDA | 2011-09-16 | 2013-05-10 | Arbor Pharmaceuticals, Inc. |
sodium nitrite | small molecules | FDA | 2007-01-17 | — | Hope Pharmaceuticals |
Poloxamer 188 | small molecules | FDA | 1997-08-05 | — | CytRx Corporation |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.