Mechanisms Of Early Brain Injury Research Articles

Monitoring of Perioperative Microcirculation Dysfunction by Near-Infrared Spectroscopy for Neurological Deterioration and Prognosis of Aneurysmal Subarachnoid Hemorrhage: An Observational, Longitudinal Cohort Study.

No evidence has established a direct causal relationship between early microcirculation disturbance after aneurysmal subarachnoid hemorrhage (aSAH) and neurological function prognosis, which is the key pathophysiological mechanism of early brain injury (EBI) in patients with aSAH. A total of 252 patients with aSAH were enrolled in the Neurosurgical Intensive Care Unit of Southwest Hospital between January 2020 and December 2022 and divided into the no neurological deterioration, early neurological deterioration, and delayed neurological deterioration groups. Indicators of microcirculation disorders in EBI included regional cerebral oxygen saturation (rSO2) measured by near-infrared spectroscopy (NIRS), brain oxygen monitoring, and other clinical parameters for evaluating neurological function and determining the prognosis of patients with aSAH. Our data suggest that the rSO2 is generally lower in patients who develop neurological deterioration than in those who do not and that there is at least one time point in the population of patients who develop neurological deterioration where left and right cerebral hemisphere differences can be significantly monitored by NIRS. An unordered multiple-classification logistic regression model was constructed, and the results revealed that multiple factors were effective predictors of early neurological deterioration: reoperation, history of brain surgery, World Federation of Neurosurgical Societies (WFNS) grade4-5, Fisher grade3-4, SAFIRE grade 3-5, abnormal serum sodium and potassium levels, and reduced rSO2 during the perioperative period. However, for delayed neurological deterioration in patients with aSAH, only a history of brain surgery and perioperative RBC count were predictive indicators. The rSO2 concentration in patients with neurological deterioration is generally lower than that in patients without neurological deterioration, and at least one time point in the population with neurological deterioration can be significantly monitored via NIRS. However, further studies are needed to determine the role of microcirculation and other predictive factors in the neurocritical management of EBI after aSAH, as these factors can reduce the incidence of adverse outcomes and mortality during hospitalization.

Sirtuins as Potential Targets for Neuroprotection: Mechanisms of Early Brain Injury Induced by Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a prevalent cerebrovascular disease with significant global mortality and morbidity rates. Despite advancements in pharmacological and surgical approaches, the quality of life for SAH survivors has not shown substantial improvement. Traditionally, vasospasm has been considered a primary contributor to death and disability following SAH, but anti-vasospastic therapies have not demonstrated significant benefits for SAH patients' prognosis. Emerging studies suggest that early brain injury (EBI) may play a crucial role in influencing SAH prognosis. Sirtuins (SIRTs), a group of NAD + -dependent deacylases comprising seven mammalian family members (SIRT1 to SIRT7), have been found to be involved in neural tissue development, plasticity, and aging. They also exhibit vital functions in various central nervous system (CNS) processes, including cognition, pain perception, mood, behavior, sleep, and circadian rhythms. Extensive research has uncovered the multifaceted roles of SIRTs in CNS disorders, offering insights into potential markers for pathological processes and promising therapeutic targets (such as SIRT1 activators and SIRT2 inhibitors). In this article, we provide an overview of recent research progress on the application of SIRTs in subarachnoid hemorrhage and explore their underlying mechanisms of action.

Early Brain Injury After Subarachnoid Hemorrhage: Incidence and Mechanisms.

Aneurysmal subarachnoid hemorrhage is a devastating condition causing significant morbidity and mortality. While outcomes from subarachnoid hemorrhage have improved in recent years, there continues to be significant interest in identifying therapeutic targets for this disease. In particular, there has been a shift in emphasis toward secondary brain injury that develops in the first 72 hours after subarachnoid hemorrhage. This time period of interest is referred to as the early brain injury period and comprises processes including microcirculatory dysfunction, blood-brain-barrier breakdown, neuroinflammation, cerebral edema, oxidative cascades, and neuronal death. Advances in our understanding of the mechanisms defining the early brain injury period have been accompanied by improved imaging and nonimaging biomarkers for identifying early brain injury, leading to the recognition of an elevated clinical incidence of early brain injury compared with prior estimates. With the frequency, impact, and mechanisms of early brain injury better defined, there is a need to review the literature in this area to guide preclinical and clinical study.

Biological Effects and Mechanisms of Caspases in Early Brain Injury after Subarachnoid Hemorrhage

Caspases are an evolutionarily conserved family of proteases responsible for mediating and initiating cell death signals. In the past, the dysregulated activation of caspases was reported to play diverse but equally essential roles in neurodegenerative diseases, such as brain injury and neuroinflammatory diseases. A subarachnoid hemorrhage (SAH) is a traumatic event that is either immediately lethal or induces a high risk of stroke and neurological deficits. Currently, the prognosis of SAH after treatment is not ideal. Early brain injury (EBI) is considered one of the main factors contributing to the poor prognosis of SAH. The mechanisms of EBI are complex and associated with oxidative stress, neuroinflammation, blood-brain barrier disruption, and cell death. Based on mounting evidence, caspases are involved in neuronal apoptosis or death, endothelial cell apoptosis, and increased inflammatory cytokine-induced by apoptosis, pyroptosis, and necroptosis in the initial stages after SAH. Caspases can simultaneously mediate multiple death modes and regulate each other. Caspase inhibitors (including XIAP, VX-765, and Z-VAD-FMK) play an essential role in ameliorating EBI after SAH. In this review, we explore the related pathways mediated by caspases and their reciprocal regulation patterns after SAH. Furthermore, we focus on the extensive crosstalk of caspases as a potential area of research on therapeutic strategies for treating EBI after SAH.

The Role of ET-1 in Early Cerebral Microcirculation Changes after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH), especially aneurysmal subarachnoid hemorrhage, is a serious cerebrovascular disease with high mortality and morbidity. However, there is no effective treatment in clinics. In recent years, more and more studies have shown that early brain injury (EBI) may be an important reason for poor prognosis of SAH. Explore the mechanism of early brain injury after subarachnoid hemorrhage (SAH). In this study, 20 male New Zealand white rabbits were selected and divided into the experimental group and sham operation group, with 10 rabbits in each group. The neurobehavioral scores, food intake, and cerebral perfusion parameters, cerebral blood volume (CBV), cerebral blood flow velocity (CBF), ET-1, IL-1, and IL-6, in rabbit plasma were compared. The food intake scores and neurological dysfunction scores of the experimental group at 1 h, 6 h, 24 h, and 72 h after modeling were higher than those of the sham operation group, which had a statistical significance (P < 0.05). The dysfunction scores all showed a gradual decrease; the CBV and CBF values of the experimental group at 1 h, 6 h, 24 h, and 72 h after modeling were all lower than those of the sham operation group, which had a statistical significance (P < 0.05), and the MTT values were all higher than that of the sham operation group, which had a statistical significance (P < 0.05). The TTP values of rats in the experimental group were higher than those in the sham operation group at 6 h, 24 h, and 72 h after modeling (P < 0.05), the experimental group was in the modeling. The levels of serum ET-1, IL-1, and IL-6 at 1 h, 6 h, 24 h, and 72 h were higher than those in the sham operation group, which had a statistical significance (P < 0.05). New Zealand white rabbits can have brain perfusion volume disorder, inflammatory reaction, and cerebral vasospasm in the early stage after SAH, and brain injury can appear in the early stage.

Effect of Puerarin on EBI after SAH

Objective The neuroinflammatory reaction activated after the activation of microglia plays a critical role in the pathological mechanism of early brain injury after subarachnoid hemorrhage. The inhibitory effect of Puerarin on inflammatory response plays a protective effect against various diseases. The present study mainly explored whether Puerarin alleviates the inflammation after SAH by inhibiting the Notchl pathway. Methods: Rat SAH model was induced by internal carotid artery puncture. The content of brain edema was evaluated and assessed. Evans blue staining was used to detect the degree of blood-brain barrier damage. FJC staining was used to assess neuronal apoptosis. Western blot method was employed to detect the expressions of Notchl receptor and downstream factors to clarify the protective effect and specific mechanism of Puerarin on brain tissue after SAH. Results: Puerarin can attenuate the brain edema and blood-brain barrier damage caused by early brain injury within 72 h after SAH, reduce the contents of Ibal and CD68 positive microglia. Intraventricular injection of Notchl receptor blockers and Notchl siRNA can inhibit the activation of Notchl pathway after SAH, mitigate brain tissue edema, blood-brain barrier damage, and neuronal apoptosis, as well as inhibit the activation of microglia and the release of inflammatory factors. Puerarin can inhibit the activation of Notchl receptor and downstream pathways, and simultaneously increase the content of Botch in brain tissue. Conclusion: Puerarin can inhibit the activation of Notchl receptor through Botch factor, thereby inhibiting the neuroinflammatory reaction mediated by Notchl pathway, and finally improve the early neurological dysfunction after SAH.

Characteristics of MRI Findings after Subarachnoid Hemorrhage and D-Dimer as a Predictive Value for Early Brain Injury

BackgroundThe pathological mechanisms of early brain injury (EBI) have remained obscure. Several studies have reported on the neuroradiological findings of EBI. However, to our knowledge, no study has attempted to explore the mechanism of EBI after subarachnoid hemorrhage (SAH). Therefore, this study evaluates whether the initial plasma D-dimer levels were associated with EBI, classifies magnetic resonance imaging (MRI) findings, and speculates about the mechanism of EBI. MethodsThis study included 97 patients hospitalized within 24 h from the onset of nontraumatic SAH. The patients underwent MRI within 0–5 days from onset (before vasospasm) to detect EBI. EBI was radiologically defined as diffusion-weighted imaging (DWI)-positive lesions that appear dark on apparent diffusion coefficient maps, excluding procedure-related lesions. EBI, plasma D-dimer levels, and clinical features were retrospectively investigated. ResultsElevated D-dimer levels were associated with poor outcomes. Patients with EBI had significantly higher D-dimer levels than those without EBI. EBI was detected in 24 patients (27.3%) of all, and in 22 (45%) of 49 patients with World Federation of Neurosurgical Societies (WFNS) grade 4–5 SAH. EBI was frequently observed in the paramedian frontal lobe. There were several types of the pathology in EBI, including widespread symmetrical cerebral cortex lesions, focal cortex lesions, periventricular injury, and other lesions impossible to classify due to unknown mechanisms such as thrombotic complication and microcirculatory disturbance, ultra-early spasm, and spreading depolarization. ConclusionsThis study suggests that D-dimer levels predict poor outcomes in patients with SAH and that EBI was associated high D-dimer levels.

Higher Serum Levels of Lactate Dehydrogenase Before Microsurgery Predict Poor Outcome of Aneurysmal Subarachnoid Hemorrhage.

Introduction: We explored whether higher preoperative serum levels of lactate dehydrogenase (LDH) predicted outcome 3 months after surgery in patients with aneurysmal subarachnoid hemorrhage (aSAH) treated using microsurgical clipping in our institution.Methods: Patients with aSAH treated at our institution between 2010 and 2018 were enrolled. The following parameters were recorded: age, sex, smoking and drinking history, medical history, Hunt–Hess and Fisher grades, aneurysm location, aneurysm size, surgical treatment, delayed cerebral ischemia (DCI), intracranial infection, hydrocephalus, pneumonia, and preoperative serum LDH levels within 24 h of aSAH. We investigated whether preoperative serum LDH levels were associated with Hunt–Hess grade, Fisher grade, and functional neurological outcome.Results: In total, 2,054 patients with aSAH were enrolled, 874 of whom were treated using microsurgical clipping. The average serum LDH level (U/L) was significantly lower in the good outcome group (180.096 ± 50.237) than in the poor outcome group (227.554 ± 83.002; p < 0.001). After propensity score matching, the average serum LDH level (U/L) was still lower in the good outcome group (205.356 ± 76.785) than in the poor outcome group (227.119 ± 86.469; p = 0.029). The area under the receiver operating characteristic (ROC) curve was 0.702 (95% confidence interval [CI]: 0.650–0.754; p < 0.001). Based on the ROC curve, the optimal cutoff value for serum LDH levels as a predictor of poor 3-month outcome (modified Rankin Scale score > 2) was 201.5 U/L. The results revealed that Hunt–Hess grade, Fisher grade, DCI, pneumonia, and serum LDH (>201.5 U/L) were significantly associated with poor outcome. After propensity score matching, serum LDH levels > 201.5 U/L were still considered an independent risk factor for poor outcome (odds ratio: 2.426, 95% CI = 1.378–4.271, p = 0.002). Serum LDH levels were associated with Hunt–Hess and Fisher grades and were correlated with functional neurological outcomes (p < 0.001).Conclusions: Our findings showed that higher preoperative serum levels of LDH correlated with Hunt–Hess grade, Fisher grade, and neurological functional outcome, and predicted the outcome of aSAH treated by microsurgical clipping at 3 months, which was involved in the related mechanisms of early brain injury and showed its potential clinical significance in patients with aSAH.

Fluid metabolic pathways after subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular disease with high mortality and morbidity. In recent years, a large number of studies have focused on the mechanism of early brain injury (EBI) and delayed cerebral ischemia (DCI), including vasospasm, neurotoxicity of hematoma and neuroinflammatory storm, after aSAH. Despite considerable efforts, no novel drugs have significantly improved the prognosis of patients in phase III clinical trials, indicating the need to further re-examine the multifactorial pathophysiological process that occurs after aSAH. The complex pathogenesis is reflected by the destruction of the dynamic balance of the energy metabolism in the nervous system after aSAH, which prevents the maintenance of normal neural function. This review focuses on the fluid metabolic pathways of the central nervous system (CNS), starting with ruptured aneurysms, and discusses the dysfunction of blood circulation, cerebrospinal fluid (CSF) circulation and the glymphatic system during disease progression. It also proposes a hypothesis on the metabolic disorder mechanism and potential therapeutic targets for aSAH patients. Cover Image for this issue:https://doi.org/10.1111/jnc.15384.

The Updated Role of the Blood Brain Barrier in Subarachnoid Hemorrhage: From Basic and Clinical Studies.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke associated with high mortality and morbidity. The blood-brain-barrier (BBB) is a structure consisting primarily of cerebral microvascular endothelial cells, end feet of astrocytes, extracellular matrix, and pericytes. Post-SAH pathophysiology included early brain injury and delayed cerebral ischemia. BBB disruption was a critical mechanism of early brain injury and was associated with other pathophysiological events. These pathophysiological events may propel the development of secondary brain injury, known as delayed cerebral ischemia. Imaging advancements to measure BBB after SAH primarily focused on exploring innovative methods to predict clinical outcome, delayed cerebral ischemia, and delayed infarction related to delayed cerebral ischemia in acute periods. These predictions are based on detecting abnormal changes in BBB permeability. The parameters of BBB permeability are described by changes in computed tomography (CT) perfusion and magnetic resonance imaging (MRI). Kep seems to be a stable and sensitive indicator in CT perfusion, whereas Ktrans is a reliable parameter for dynamic contrast-enhanced MRI. Future prediction models that utilize both the volume of BBB disruption and stable parameters of BBB may be a promising direction to develop practical clinical tools. These tools could provide greater accuracy in predicting clinical outcome and risk of deterioration. Therapeutic interventional exploration targeting BBB disruption is also promising, considering the extended duration of post-SAH BBB disruption.

HLY78 Attenuates Neuronal Apoptosis via the LRP6/GSK3β/β-Catenin Signaling Pathway After Subarachnoid Hemorrhage in Rats.

Neuronal apoptosis is one of the essential mechanisms of early brain injury after subarachnoid hemorrhage (SAH). Recently, HLY78 has been shown to inhibit apoptosis in tumor cells and embryonic cells caused by carbon ion radiation through activation of the Wnt/β-catenin pathway. This study was designed to explore the anti-apoptotic role of HLY78 in experimental SAH. The results demonstrated that HLY78 attenuated neuronal apoptosis and the neurological deficits after SAH through the activation of low-density lipoprotein receptor-related protein 6 (LRP6), which subsequently increased the level of phosphorylated glycogen synthesis kinase 3 beta (p-GSK3β) (Ser9), β-catenin, and Bcl-2, accompanied by a decrease of p-β-catenin, Bax, and cleaved caspase 3. An LRP6 small-interfering ribonucleic acid reversed the effects of HLY78. In conclusion, HLY78 attenuates neuronal apoptosis and improves neurological deficits through the LRP6/GSK3β/β-catenin signaling pathway after SAH in rats. HLY78 is a promising therapeutic agent to attenuate early brain injury after SAH.

The Potential Value of Targeting Ferroptosis in Early Brain Injury After Acute CNS Disease.

Acute central nervous system (CNS) disease is very common and with high mortality. Many basic studies have confirmed the molecular mechanism of early brain injury (EBI) after acute CNS disease. Neuron death and dysfunction are important reasons for the neurological dysfunction in patients with acute CNS disease. Ferroptosis is a nonapoptotic form of cell death, the classical characteristic of which is based on the iron-dependent accumulation of toxic lipid reactive oxygen species. Previous studies have indicated that this mechanism is critical in the cell death events observed in many diseases, including cancer, tumor resistance, Alzheimer’s disease, Parkinson’s disease, stroke, and intracerebral hemorrhage (ICH). Ferroptosis may also play a very important role in EBI after acute CNS disease. Unresolved issues include the relationship between ferroptosis and other forms of cell death after acute CNS disease, the specific molecular mechanisms of EBI, the strategies to activate or inhibit ferroptosis to achieve desirable attenuation of EBI, and the need to find new molecular markers of ferroptosis that can be used to detect and study this process in vivo after acute CNS disease.

Neuroinflammation and Microvascular Dysfunction After Experimental Subarachnoid Hemorrhage: Emerging Components of Early Brain Injury Related to Outcome.

Aneurysmal subarachnoid hemorrhage has a high mortality rate and, for those who survive this devastating injury, can lead to lifelong impairment. Clinical trials have demonstrated that cerebral vasospasm of larger extraparenchymal vessels is not the sole contributor to neurological outcome. Recently, the focus of intense investigation has turned to mechanisms of early brain injury that may play a larger role in outcome, including neuroinflammation and microvascular dysfunction. Extravasated blood after aneurysm rupture results in a robust inflammatory response characterized by activation of microglia, upregulation of cellular adhesion molecules, recruitment of peripheral immune cells, as well as impaired neurovascular coupling, disruption of the blood-brain barrier, and imbalances in endogenous vasodilators and vasoconstrictors. Each of these phenomena is either directly or indirectly associated with neuronal death and brain injury. Here, we review recent studies investigating these various mechanisms in experimental models of subarachnoid hemorrhage with special emphasis on neuroinflammation and its effect on microvascular dysfunction. We discuss the various therapeutic targets that have risen from these mechanistic studies and suggest the utility of a multi-targeted approach to preventing delayed injury and improving outcome after subarachnoid hemorrhage.

Mitoquinone attenuates blood-brain barrier disruption through Nrf2/PHB2/OPA1 pathway after subarachnoid hemorrhage in rats

Background and purposeMitochondrial dysfunction is involved in the mechanism of early brain injury (EBI) following subarachnoid hemorrhage (SAH). Blood-brain barrier disruption is a devastating outcome in the early stage of SAH. In this study, we aimed to investigate the role of a mitochondria-related drug Mitoquinone (MitoQ) in blood-brain barrier disruption after SAH in rats. MethodsA total of 181 male Sprague–Dawley SAH rats with the endovascular perforation model were utilized. Intraperitoneal MitoQ was given 1 h (h) post-SAH. Cerebroventricular ML385, an inhibitor of NF-E2-related factor 2 (Nrf2) and Small interfering ribonucleic acid (siRNA) for Prohibitin 2 (PHB2) were injected respectively 24 h and 48 h before SAH. Neurological function evaluation was performed before sacrifice. SAH grade was measured during the sacrifice of each animal. Brain water content was performed at 24 h. Co-immunoprecipitation was used to demonstrate the relationship of proteins Nrf2 and PHB2. Mitochondrial and cytoplasmic fractions were gathered using mitochondria isolation kits. Pathway related proteins were investigated with Western blot and immunofluorescence staining. Transmission electron microscopy was performed for mitochondrial morphology. ResultsExpression of Nrf2 levels peaked at the 3 h time point following SAH and then decreased to normal levels at 24 h, while PHB2 and Optic Atrophy 1 (OPA1) decreased at 24 h and 72 h after SAH compared with the Sham group. MitoQ treatment attenuated neurological deficits and brain edema, thereby resulting in a decreased expression of Albumin, while an increase of Nrf2, PHB2, OPA1 and Claudin-5 proteins compared with SAH + vehicle group. With co-immunoprecipitation, Nrf2 and PHB2 were further demonstrated to show their interaction. And MitoQ administration lead to more binding of the two proteins. ML385 abolished the effects of MitoQ on neurobehavior and protein levels post-SAH. Similarly, PHB2 siRNA reversed the neuroprotection of MitoQ administration with the decreased expression of PHB2 and OPA1 after SAH. Further, MitoQ treatment improved mitochondrial morphology after SAH with an increase of PHB2 and OPA1 in mitochondrial extraction. ConclusionsMitoQ attenuates blood-brain barrier disruption via Nrf2/PHB2/OPA1 pathway after SAH in rats. MitoQ may serve as a potential therapeutic strategy for SAH patients.

The decrease of Tie-2 receptor phosphorylation in microvascular endothelial cells is involved in early brain injury after subarachnoid hemorrhage

PurposeLoose endothelial cells and the destruction of the blood–brain barrier (BBB) are one of the pathophysiological mechanisms of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Tie-2 receptor phosphorylation is important for maintaining integrity of microvascular endothelial cells and BBB. This study aimed to explore the role and changes of Tie-2 receptor phosphorylation levels in EBI after SAH. MethodsThis study used an endovascular puncture model of rat to simulate the occurrence and development of aneurysmal subarachnoid hemorrhage. The location of Tie-2 receptor in brain tissues was determined by immunofluorescence. Immunofluorescence and western blot was carried out to observe the expression of Claudin-5 and Occludin in cortex and hippocampus. We chose to observe the Tie-2 receptor phosphorylation level in hippocampus according western blot. Evans blue viability assay was used to evaluate BBB permeability. ResultsThe results suggested that Tie-2 receptor mainly expressed around the vascular endothelial cells in brain. Following SAH, the Tie-2 receptor phosphorylation level and expression of tight junction protein (claudin-5 and occluding) decreased. Both of these downtrends were reversed by exogenous Angiopoietin-1 (Ang-1). Finally, injection of exogenous Ang-1 reduced SAH-associated BBB leakage. ConclusionsOur study indicated that Tie-2 receptor phosphorylation in microvascular endothelial cells was involved in pathophysiological process after SAH, and the decline of Tie-2 receptor phosphorylation might increase blood–brain barrier permeability by decreasing the tight junction protein expression.

Unique Contribution of Haptoglobin and Haptoglobin Genotype in Aneurysmal Subarachnoid Hemorrhage.

Survivors of cerebral aneurysm rupture are at risk for significant morbidity and neurological deficits. Much of this is related to the effects of blood in the subarachnoid space which induces an inflammatory cascade with numerous downstream consequences. Recent clinical trials have not been able to reduce the toxic effects of free hemoglobin or improve clinical outcome. One reason for this may be the inability to identify patients at high risk for neurologic decline. Recently, haptoglobin genotype has been identified as a pertinent factor in diabetes, sickle cell, and cardiovascular disease, with the Hp 2-2 genotype contributing to increased complications. Haptoglobin is a protein synthesized by the liver that binds free hemoglobin following red blood cell lysis, and in doing so, prevents hemoglobin induced toxicity and facilitates clearance. Clinical studies in patients with subarachnoid hemorrhage indicate that Hp 2-2 patients may be a high-risk group for hemorrhage related complications and poor outcome. We review the relevance of haptoglobin in subarachnoid hemorrhage and discuss the effects of genotype and expression levels on the known mechanisms of early brain injury (EBI) and cerebral ischemia after aneurysm rupture. A better understanding of haptoglobin and its role in preventing hemoglobin related toxicity should lead to novel therapeutic avenues.

Possible Role of Inflammation and Galectin-3 in Brain Injury after Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is known as one of the most devastating diseases in the central nervous system. In the past few decades, research on SAH has focused on cerebral vasospasm to prevent post-SAH delayed cerebral ischemia (DCI) and to improve outcomes. However, increasing evidence has suggested that early brain injury (EBI) is an important mechanism contributing to DCI, cerebral vasospasm as well as poor outcomes. Though the mechanism of EBI is very complex, inflammation is thought to play a pivotal role in EBI. Galectin-3 is a unique chimera type in the galectin family characterized by its β-galactoside-binding lectin, which mediates various pathologies, such as fibrosis, cell adhesion, and inflammation. Recently, two clinical studies revealed galectin-3 to be a possible prognostic biomarker in SAH patients. In addition, our recent report suggested that higher acute-stage plasma galectin-3 levels correlated with subsequent development of delayed cerebral infarction that was not associated with vasospasm in SAH patients. We review the possible role and molecular mechanisms of inflammation as well as galectin-3 in brain injuries, especially focusing on EBI after SAH, and discuss galectin-3 as a potential new therapeutic or research target in post-SAH brain injuries.

Early Brain Injury or Vasospasm? An Overview of Common Mechanisms.

Subarachnoid hemorrhage (SAH) following rupture of an intracranial is associated with high mortality and morbidity. The late deterioration of the patient's neurological status or late cognitive dysfunctions even after secure clipping or decent endovascular treatment which is defined as delayed ischemic neurological deficits recently has been attributed to vasospasm. Due to the failure of specific anti- vasospastic agents in clinical trials researchers focused to explore new pathological mechanisms to be responsible for the delayed deterioration of the patients suffering from SAH. Early brain injury (EBI), as a new term in the SAH research area has been the focus of scientist for the past couple of years. The goal of this study is to review the common mechanisms of early brain injury and vasospasm. The acute events following SAH, such as increased intracranial pressure and decreased cerebral blood flow, causing global cerebral ischemia initiate a cascade of pathological changes including inflammation, lipid peroxidation, cell death and blood brain barrier disruption. The more insight we gain into the EBI we realize that there are a bunch of common mechanisms between EBI and vasospasm. In the SAH management, a therapy targeting these early injuries may also reduce the later developing pathological neurological complications.

Acute Cytotoxic and Vasogenic Edema after Subarachnoid Hemorrhage: A Quantitative MRI Study.

The mechanism of early brain injury following subarachnoid hemorrhage is not well understood. We aimed to evaluate if cytotoxic and vasogenic edema are contributing factors. A retrospective analysis was conducted in patients with SAH undergoing diffusion-weighted MR imaging within 72 hours of onset. Apparent diffusion coefficient values derived from DWI were evaluated by using whole-brain histograms and 19 prespecified ROIs in patients with SAH and controls with normal findings on MRI. Cytotoxic edema observed outside the ROIs was assessed in patients with SAH. The average median ADC values were compared between patients with SAH and controls and patients with SAH with mild (Hunt and Hess 1-3) versus severe early brain injury (Hunt and Hess 4-5). We enrolled 33 patients with SAH and 66 controls. The overall average median whole-brain ADC was greater for patients with SAH (808 × 10-6 mm2/s) compared with controls (788 × 10-6 mm2/s, P < .001) and was higher in patients with SAH across ROIs after adjusting for age: cerebral gray matter (826 versus 803 × 10-6 mm2/s, P = .059), cerebral white matter (793 versus 758 × 10-6 mm2/s, P = .023), white matter tracts (797 versus 739 × 10-6 mm2/s, P < .001), and deep gray matter (754 versus 713 × 10-6 mm2/s, P = .016). ADC values trended higher in patients with Hunt and Hess 4-5 versus those with Hunt and Hess 1-3. Early cytotoxic edema was observed in 13 (39%) patients with SAH and was more prevalent in those with severe early brain injury (87.5% of patients with Hunt and Hess 4-5 versus 24.0% of those with Hunt and Hess 1-3, P = .001). Age-adjusted ADC values were globally increased in patients with SAH compared with controls, even in normal-appearing brain regions, suggesting diffuse vasogenic edema. Cytotoxic edema was also present in patients with SAH and correlated with more severe early brain injury.

The Role of Platelet Activation and Inflammation in Early Brain Injury Following Subarachnoid Hemorrhage.

Early brain injury (EBI) following aneurysmal subarachnoid hemorrhage (SAH) is an important predictor of poor functional outcome, yet the underlying mechanism is not well understood. Animal studies suggest that platelet activation and inflammation with subsequent microthrombosis and ischemia may be a mechanism of EBI. A prospective, hypothesis-driven study of spontaneous, SAH patients and controls was conducted. Platelet activation [thromboelastography maximum amplitude (MA)] and inflammation [C-reactive protein (CRP)] were measured serially over time during the first 72h following SAH onset. Platelet activation and inflammatory markers were compared between controls and SAH patients with mild [Hunt-Hess (HH) 1-3] versus severe (HH 4-5) EBI. The association of these biomarkers with 3-month functional outcomes was evaluated. We enrolled 127 patients (106 SAH; 21 controls). Platelet activation and CRP increased incrementally with worse EBI/HH grade, and both increased over 72h (all P<0.01). Both were higher in severe versus mild EBI (MA 68.9 vs. 64.8mm, P=0.001; CRP 12.5 vs. 1.5mg/L, P=0.003) and compared to controls (both P<0.003). Patients with delayed cerebral ischemia (DCI) had more platelet activation (66.6 vs. 64.9 in those without DCI, P=0.02) within 72h of ictus. At 3months, death or severe disability was more likely with higher levels of platelet activation (mRS4-6 OR 1.18, 95% CI 1.05-1.32, P=0.007) and CRP (mRS4-6 OR 1.02, 95% CI 1.00-1.03, P=0.041). Platelet activation and inflammation occur acutely after SAH and are associated with worse EBI, DCI and poor 3-month functional outcomes. These markers may provide insight into the mechanism of EBI following SAH.