Resolution Of Hematoma Research Articles

Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice

BackgroundIntracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated.MethodsC57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism.ResultsMas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3–5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH.ConclusionsMas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

105 Creation and Optimization of a Translational Rodent Model of Cerebrovascular Disease

INTRODUCTION: Spontaneous intracerebral hemorrhage (ICH) continues to have devastating morbidity and mortality, with little progress in managing resultant secondary injury. We have created a cardiometabolic model of ICH using transgenic (mRen2)27 rats to mirror the comorbidities of patients with ICH. METHODS: Body weight, blood pressures (BP), sensorimotor testing, cerebrovascular histology, and pro-inflammatory cytokines were quantified in (mRen2)27 and compared with control Hanover Sprague Dawley (SD) in both sexes (n = 32). A stereotaxically-assisted single-injection autologous-blood ICH in the basal ganglia was performed and hemoglobin quantified at 24/72 hours to assess reabsorption (n = 28). RESULTS: Mean blood pressures and weights were higher in the cardiometabolic (mRen2)27 strain at baseline (p < 0.005). There were no between-strain differences in sensorimotor testing up to 28 weeks. At 30 weeks, (mRen2)27s had higher serum IL-12 than SDs in both males (p < 0.05) and females (p < 0.05). (mRen2)27 females had higher IL-12 than males (p < 0.05). At 32-weeks, (mRen2)27 males (p < 0.0001) had increased wall to lumen ratios (W:L), signifying hyalinization. At 52-weeks, there was an increase in W:L ratio in both male (p < 0.01) and female (p < 0.05) (mRen2)27s compared to control. There was a difference in amount of residual hemoglobin between male SD and (mRen2)27’ ipsilateral hemispheres 72 hours post-ICH (p < 0.05), demonstrating impaired ICH resolution. CONCLUSIONS: There is a need for effective pre-clinical models of ICH. We characterized a cardiometabolic model of ICH that possesses parody at baseline with the traditional rodent model and demonstrates significant strain and sex differences after ICH. (mRen2)27s had delayed hematoma resolution, decrease-in-function morphological changes, and pro-inflammatory cytokine upregulation. These differences provide insight into the mechanism of cerebrovascular injury and may act as targets for translational therapeutics.

Abstract WP163: Therapeutic Efficacy and Safety Evaluation of Cilostazol for Intracerebral Hemorrhage Through Enhancing Meningeal Lymphatic Function: A Preclinical Study

Background: Intracerebral hemorrhage (ICH) is the deadliest form of stroke with no effective treatment to date. Toxic byproducts from hematoma-lysis affected ICH-induced brain injury and long-term behavioral impairment. Enhancing hematoma clearance has shown therapeutic potential in reducing brain damage and neurologic deficits. Our previous work shows that cilostazol (CSZ) promotes meningeal lymphangiogenesis and drainage, aiding hematoma resolution and brain recovery after ICH. Here we explore the optimal dosage, therapeutic window, and potential adverse effects of CSZ treatment in preclinical ICH. Methods: A dose of 200 mg/day CSZ is used in clinics which translates to around 40 mg/kg in mice. CSZ (10, 20, and 40 mg/kg) or vehicle was given after ICH induction and was continued for various durations. Pretreatment of CSZ before ICH induction was used to assess its antiplatelet property on intra-parenchymal bleeding. Meningeal lymphatic vessel (mLV) complexity and coverage rate were measured. Lymphatic drainage was evaluated by fluorescent microbead accumulation in the mLV and deep cervical lymph nodes. Neurobehaviors were tested by corner turn test, whisker-evoked tactile responses, hindlimb abduction test, and neurologic deficit scoring. Iron deposition, hematoma, and neuron loss were assessed by immunohistochemistry. Results: ICH mice treated with CSZ showed enhanced mLV complexity and proliferation at the transverse, superior sagittal, and confluence of sinuses in the meninges. In parallel, histological, and behavioral outcomes also improved. Pretreatment with CSZ for 3 days before ICH induction did not increase hematoma volume, suggesting minimal to no adverse anticoagulant effect of CSZ in this setting. Conclusion: In all, our results unfold the effects of CSZ on mLV function regarding ICH. These findings may be applied as outcome parameters and provide a roadmap for sample size estimation in future clinical trials using CSZ as ICH treatment.

Multimodality management for chronic subdural hematoma in China: protocol and characteristics of an ambidirectional, nationwide, multicenter registry study

BackgroundDespite its prevalence, there is ongoing debate regarding the optimal management strategy for chronic subdural hematoma (CSDH), reflecting the variability in clinical presentation and treatment outcomes. This ambidirectional, nationwide, multicenter registry study aims to assess the efficacy and safety of multimodality treatment approaches for CSDH in the Chinese population.Methods/designA multicenter cohort of CSDH patients from 59 participating hospitals in mainland China was enrolled in this study. The treatment modalities encompassed a range of options and baseline demographics, clinical characteristics, radiographic findings, and surgical techniques were documented. Clinical outcomes, including hematoma resolution, recurrence rates, neurological status, and complications, were assessed at regular intervals during treatment, 3 months, 6 months, 1 year, and 2 years follow-up.ResultBetween March 2022 and August 2023, a comprehensive cohort comprising 2173 individuals who met the criterion was assembled across 59 participating clinical sites. Of those patients, 81.1% were male, exhibiting an average age of 70.12 ± 14.53 years. A historical record of trauma was documented in 48.0% of cases, while headache constituted the predominant clinical presentation in 58.1% of patients. The foremost surgical modality employed was the burr hole (61.3%), with conservative management accounting for 25.6% of cases. Notably, a favorable clinical prognosis was observed in 88.9% of CSDH patients at 3 months, and the recurrence rate was found to be 2.4%.ConclusionThis registry study provides critical insights into the multimodality treatment of CSDH in China, offering a foundation for advancing clinical practices, optimizing patient management, and ultimately, improving the quality of life for individuals suffering from this challenging neurosurgical condition.Trial registrationChiCTR2200057179

Cofilin Inhibitor Improves Neurological and Cognitive Functions after Intracerebral Hemorrhage by Suppressing Endoplasmic Reticulum Stress Related-Neuroinflammation.

Neuroinflammation after intracerebral hemorrhage (ICH) is a crucial factor that determines the extent of the injury. Cofilin is a cytoskeleton-associated protein that drives neuroinflammation and microglia activation. A novel cofilin inhibitor (CI) synthesized and developed in our lab has turned out to be a potential therapeutic agent for targeting cofilin-mediated neuroinflammation in an in vitro model of ICH and traumatic brain injury. The current study aims to examine the therapeutic potential of CI in a mouse collagenase model of ICH and examine the neurobehavioral outcomes and its mechanism of action. Male mice were subjected to intrastriatal collagenase injection to induce ICH, and sham mice received needle insertion. Various concentrations (25, 50, and 100 mg/kg) of CI were administered to different cohorts of the animals as a single intravenous injection 3 h following ICH and intraperitoneally every 12 h for 3 days. The animals were tested for neurobehavioral parameters for up to 7 days and sacrificed to collect brains for hematoma volume measurement, Western blotting, and immunohistochemistry. Blood was collected for cofilin, TNF-α, and IL-1β assessments. The results indicated that 50 mg/kg CI improved neurological outcomes, reversed post-stroke cognitive impairment, accelerated hematoma resolution, mitigated cofilin rods/aggregates, and reduced microglial and astrocyte activation in mice with ICH. Microglia morphological analysis demonstrated that CI restored the homeostasis ramification pattern of microglia in mice treated with CI. CI suppressed endoplasmic reticulum stress-related neuroinflammation by inhibiting inflammasomes and cell death signaling pathways. We also showed that CI prevented synaptic loss by reviving the pre- and post-synaptic markers. Our results unveil a novel therapeutic approach to treating ICH and open a window for using CI in clinical practice.

Charlson Comorbidity Index and Frailty as Predictors of Resolution Following Middle Meningeal Artery Embolization for Chronic Subdural Hematoma

Research on variables associated with chronic subdural hematoma (cSDH) resolution following middle meningeal artery embolization (MMAE) is limited. This study investigated the clinical utility of age-adjusted Charlson Comorbidity Index (ACCI) and modified 5-item Frailty Index (mFI-5) for predicting cSDH resolution following MMAE. We identified patients who underwent MMAE at our institution between January 2018, and December 2022, with at least 20 days of follow-up and one radiographic follow-up study. Patient demographics, characteristics, and outcomes were collected. Complete resolution was defined as absence of subdural collections on CT-scan at last follow-up. Non-age adjusted CCI (CCI), ACCI, and mFI-5 scores were calculated. Univariate and multivariable logistic regression analyzed the relationship between cSDH resolution and variables. A receiver operating characteristic (ROC) curve established the utility of ACCI and mFI-5 in predicting hematoma resolution. The study included 85 MMAE procedures. In univariate analysis, patients without resolution were older, had higher CCI, higher ACCI, higher mFI-5, and were more likely to have diabetes mellitus. In multivarible analysis, CCI (OR: 0.66, 95% CI: 0.48, 0.91) was independently associated with resolution controlling for age and antithrombotic resumption. The area under the ROC (AUROC) curve was 0.75 (95% CI: 0.65 - 0.85) for ACCI and 0.64 (95% CI: 0.52 - 0.76) for mFI-5. The optimal cutoffs for predicting resolution were ACCI ≥ 5 (sensitivity = 0.63, specificity = 0.77), and mFI-5 > 0 (sensitivity = 0.84, specificity = 0.43). ACCI and mFI-5 moderately predict MMAE resolution and may aid in medical decision-making.

Neutrophil-like pH-responsive pro-efferocytic nanoparticles improve neurological recovery by promoting erythrophagocytosis after intracerebral hemorrhage.

Rationale: Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease resulting from blood extravasating into the brain parenchyma. Escalation of erythrophagocytosis (a form of efferocytosis), avoiding the consequent release of the detrimental erythrocyte lysates, may be a promising target of ICH management. The ADAM17 inhibitor and liver X receptor (LXR) agonist could promote efficient efferocytosis and injury repair. Nevertheless, the poor bioavailability and restriction of the blood-brain barrier (BBB) hinder their application. Therefore, it is needed that biocompatible and smart nanoplatforms were designed and synthesized to realize effective therapy targeting erythrophagocytosis. Methods: We first assessed the synergistic effect of therapeutic GW280264X (an ADAM17 inhibitor) and desmosterol (an LXR agonist) on erythrophagocytosis in vitro. Then a pH-responsive neutrophil membrane-based nanoplatform (NPEOz) served as a carrier to accurately deliver therapeutic GW280264X and desmosterol to the damaged brain was prepared via co-extrusion. Afterwards, their pH-responsive performance was valued in vitro and targeting ability was assessed through fluorescence image in vivo. Finally, the pro-erythrophagocytic and anti-neuroinflammatory ability of the nanomedicine and related mechanisms were investigated. Results: After the synergistical effect of the above two drugs on erythrophagocytosis was confirmed, we successfully developed neutrophil-disguised pH-responsive nanoparticles to efficiently co-deliver them. The nanoparticles could responsively release therapeutic agents under acidic environments, and elicit favorable biocompatibility and ability of targeting injury sites. D&G@NPEOz nanoparticles enhanced erythrophagocytosis through inhibiting shedding of the efferocytotic receptors MERTK/AXL mediated by ADAM17 and accelerating ABCA-1/ABCG-1-mediated cholesterol efflux regulated by LXR respectively. In addition, the nano-formulation was able to modulate the inflammatory microenvironment by transforming efferocytes towards a therapeutic phenotype with reducing the release of proinflammatory cytokines while increasing the secretion of anti-inflammatory factors, and improve neurological function. Conclusions: This biomimetic nanomedicine is envisaged to offer an encouraging strategy to effectively promote hematoma and inflammation resolution, consequently alleviate ICH progression.

Spontaneous hematomas in COVID-19 patients. Literature review

A brief literature review presents the main classifications, clinical manifestations and methods of diagnosis of spontaneous retroperitoneal and rectus sheath hematomas in patients with COVID-19. The direct and indirect ultrasound criteria, stages of resolution and treatment strategy of the spontaneous hematomas are discussed

Clearance of Neutrophils From ICH-Affected Brain by Macrophages Is Beneficial and Is Assisted by Lactoferrin and CD91.

Within hours after intracerebral hemorrhage (ICH) onset, masses of polymorphonuclear neutrophils (PMNs) infiltrate the ICH-affected brain. After degranulation involving controlled release of many toxic antimicrobial molecules, the PMNs undergo rapid apoptosis and then are removed by phagocytic microglia/macrophages (MΦ) through a process called efferocytosis. Effective removal of PMNs may limit secondary brain damage and inflammation; however, the molecular mechanisms governing these cleanup activities are not well understood. We propose that scavenger receptor CD91 on myeloid phagocytes especially in presence of CD91 ligand, LTF (lactoferrin, protein abundant in PMNs), plays an important role in clearance of dead apoptotic PMNs (ANs). Mice/rats were subjected to an autologous blood injection model of ICH. Primary cultured microglia were used to assess phagocytosis of ANs. Immunohistochemistry was employed to assess CD91 expression and PMN infiltration. CD91 knockout mice selectively in myeloid phagocytes (Mac-CD91-KO) were used to establish the CD91/LTF function in phagocytosis and in reducing ICH-induced injury, as assessed using behavioral tests, hematoma resolution, and oxidative stress. Masses of PMNs are found in ICH-affected brain, and they contain LTF. MΦ at the outer border of hematoma are densely packed, expressing CD91 and phagocytosing ANs. Microglia deficient in CD91 demonstrate defective phagocytosis of ANs, and mice deficient in CD91 (Mac-CD91-KO) subjected to ICH injury have increased neurological dysfunction that is associated with impaired hematoma resolution (hemoglobin and iron clearance) and elevated oxidative stress. LTF that normally ameliorates ICH injury in CD91-proficient control mice shows reduced therapeutic effects in Mac-CD91-KO mice. Our study suggests that CD91 plays a beneficial role in improving ANs phagocytosis and ultimately post-ICH outcome and that the beneficial effect of LTF in ICH is in part dependent on presence of CD91 on MΦ.

Liquid embolic surface area as a predictor of chronic subdural hematoma resolution in middle meningeal artery embolization

BackgroundLiquid embolic agents (LEAs) such as ethylene vinyl alcohol (EVOH) are utilized for middle meningeal artery embolization (MMAE) for chronic subdural hematomas (cSDH). LEAs may be advantageous for MMAE as...

Correlation Between Low-Density Hematoma at 1-Week Post-Middle Meningeal Artery Embolization and Rapid Resolution of Chronic Subdural Hematoma

Temporal changes in the volume of chronic subdural hematoma (CSDH) following middle meningeal artery (MMA) embolization vary. We aimed to determine whether CSDH density on computed tomography is related to hematoma resolution following particle MMA embolization. Patients who underwent MMA embolization for CSDH were enrolled. The CSDHs were quantitatively divided into 2 hematoma groups based on the hematoma density at 1-week postembolization: low-density or high-density. The temporal change in the volume of CSDHs was then analyzed between the groups. Thirty patients were enrolled in this study. Three patients with high-density hematomas required rescue surgery. The hematoma volume was significantly lower in low-density hematomas than in high-density hematoma at 1-week (P=0.006), 1-month (P=0.003), and 2-month (P=0.004) postembolization; although the volume converged to a similar value at 3-month (P>0.05). There was a positive correlation between hematoma density at 1-week postembolization and percentage hematoma volume at 1-week and 1-month postembolization (P= 0.004 and P < 0.001, respectively), but no correlation was observed between hematoma density before MMA embolization and percentage hematoma volume at 1-week and 1-month postembolization (P= 0.54 and P= 0.17, respectively). Rapid resolution of CSDH following MMA embolization was associated with low hematoma density at 1-week postembolization. Based on hematoma density on computed tomography at 1-week postembolization, a 1-month follow-up would be sufficient in cases of low density, but a 3-month follow-up would be required in cases of high-density hematoma. Larger studies and clinical trials are needed to confirm our findings.

Long non-coding RNA MIR17HG impedes FOSL2-mediated transcription activation of HIC1 to maintain a pro-inflammatory phenotype of microglia during intracerebral haemorrhage.

Activation and polarization of microglia play decisive roles in the progression of intracerebral haemorrhage (ICH), and lactate exposure correlates with microglia polarization. This study explores molecules influencing lactate production and microglia phenotype alteration following ICH. A murine model of ICH was induced by intracerebral injection of collagenase. The mice experienced autonomous neurological function recovery, haematoma resolution and rapid lactate production, along with a gradual increase in angiogenesis activity, neuronal recovery and an M1-to-M2 phenotype change of microglia. Galloflavin, a lactate dehydrogenase antagonist, suppressed this phenotype change and the functional recovery in mice. FOS like 2 (FOSL2) was significantly upregulated in the brain tissues from day 7 post-ICH. Overexpression of FOSL2 induced an M1-to-M2 phenotype shift in microglia and accelerated lactate production in vivo and in haemoglobin-treated microglia in vitro. Long non-coding RNA MIR17HG impeded FOSL2-mediated transcription activation of hypermethylated in cancer 1 (HIC1). MIR17HG overexpression induced pro-inflammatory activation of microglia in mice, which was blocked by further HIC1 overexpression. Overall, this study demonstrates that MIR17HG maintains a pro-inflammatory phenotype of microglia during ICH progression by negating FOSL2-mediated transcription activation of HIC1. Specific inhibition of MIR17HG or upregulation of FOSL2 or HIC1 may favour inflammation inhibition and haematoma resolution in ICH.

A Rare Case of an Acquired Isolated Factor VII Deficiency was Discovered in a 23-Year-Old Female Patient

Introduction: Factor VII (FVII) deficiency, a rare bleeding disorder, can manifest as an autosomal recessive congenital or an acquired coagulopathy. Acquired FVII deficiency, although infrequently reported, presents unique challenges in understanding its mechanisms and identifying underlying causes. Case presentation: We present a case of acquired FVII deficiency discovered in a 23-year-old female patient with no apparent underlying disease. The patient exhibited spontaneous ecchymosis and gingival hemorrhage, along with low FVII activity and isolated prolongation of prothrombin time. Extensive laboratory investigations excluded liver dysfunction, familial deficiency, vitamin K deficiency, and inhibitory antibodies. Prompt treatment with Fresh Frozen Plasma (FFP) and bypassing agents resulted in a favorable response and resolution of hematomas. Conclusion: Acquired FVII deficiency was identified with bleeding symptoms in association with prolonged prothrombin time and a low level of FVII activity. In literature, this deficiency has been associated with various conditions such as sepsis, aplastic anemia, stem cell transplantation, and neoplasms, although approximately 14% of cases remain idiopathic. Clinical outcomes remain generally poor, with limited complete remissions reported.

Thrombolysis for acute myocardial infarction in early post-renal transplant period: A case report

Cardiovascular disease is a major contributor to morbidity and has become the leading cause of death among renal transplant patients. This paper presents a case of acute myocardial infarction occurring three weeks after a renal transplant. A 45-year-old male recipient experienced acute chest pain, hypotension, and atrial fibrillation, leading to a diagnosis of inferior-posterior wall myocardial infarction. Thrombolysis with Tenectaplase was administered, resulting in the development of a perinephric hematoma six hours later. The patient underwent transfusions and pigtail drainage of the hematoma. Following hematoma resolution, the pigtail catheter was removed, and the patient was started on dual anti-platelets. Upon discharge, the patient exhibited stable renal function. In conclusion, thrombolysis in the early post-transplant period poses significant risks. This case highlights the use of thrombolytic therapy during this period and the successful management of associated complications.

Improving outcomes in intracerebral hemorrhage through microglia/macrophage-targeted IL-10 delivery with phosphatidylserine liposomes

Intracerebral hemorrhage (ICH) remains the most lethal type of stroke, and effective clinical therapies that can speed up hematoma resolution after ICH are still lacking. While the beneficial effects of IL-10 on ICH recovery have been demonstrated, the clinical translation of IL-10 requires effective delivery methods by which sufficient IL-10 can be delivered to ICH-affected regions in the brain. Here we report the use of a phosphatidylserine (PS) liposome (PSL)-based nanoparticle system for microglia/macrophage-targeted delivery of IL-10 in ICH. We first prepared IL-10-conjugated PSL (PSL-IL10) and characterized their immunomodulating effects in vitro. Then we evaluated the therapeutic effects, including hematoma absorption, short-term outcomes, and neuroinflammation, of intranasally administered PSL-IL10 (3 μg IL-10 per mouse, 2 h post-ICH) in a collagenase-induced ICH mouse model. We also isolated microglia/macrophages from the mouse brains with ICH to analyze their morphology, phagocytosis ability, and polarization. Our study reveals that, 1) PSL-IL10 treatment resulted in significantly improved outcomes and accelerated hematoma resolution in the acute phase of ICH; 2) PSL-IL10 inhibited glial activation and down-regulated pro-inflammatory cytokine production; 3) PSL-IL10 induced Iba1+ cells with a stronger phagocytosis ability; 4) PSL-IL10 activated STAT3 and upregulated CD36 expression in microglia/macrophage. These findings collectively show that PSL-IL10 is a promising nanotherapeutic for effectively ameliorating ICH.

Natural course of chronic subdural hematoma following surgical clipping of unruptured intracranial aneurysm by pterional approach.

Chronic subdural hematoma (CSDH) is a neurological complication following clipping surgery. However, the natural course and ideal approach for the treatment of clipping-related-CSDH (CR-CSDH) have not been clearly established. We aimed to investigate the course of CR-CSDH using chronological radiological findings. We performed a retrospective analysis of 28 (3.8%) patients who developed CSDH among 736 patients who underwent surgical clipping using pterional approach for unruptured aneurysms at our institution between December 2010 and December 2018. Patients underwent follow-up CT scan 6-8 weeks after clipping surgery and decision to pursue surgical intervention rests upon the patient's symptom based on the Markwalder's grading scale (MGS) and numeric rating scale (NRS). Of the 28 patients, 3 patients (10.7%) underwent surgery, while 25 (89.2%) showed spontaneous resolution of CR-CSDH. Eighteen patients (64.2%) had mild headache with MGS of 0-1. The mean maximum hematoma volume was 41.9±30.9 ml (5.8-135 ml), and 26 patients (92.8%) had homogeneous hematoma. The mean time to hematoma resolution was 126.7±52.9 days (46-228 days). Comparing group of CR-CSDH volume ≥43 ml or a midline shift ≥5 mm, the difference in presence of linear low-density area (p=0.002) and age (p=0.026) between the conservative and operative groups were found to be statistically significant. Most CR-CSDH cases spontaneously resolved within 4 months. Therefore, we suggest that close observation should be performed if patient's symptoms are mild and special radiologic findings are present, despite its relatively large volume and midline shifting.

Urokinase administration for intraventricular hemorrhage in adults: A retrospective analysis of hemorrhage volume reduction and clinical outcomes.

Intraventricular hemorrhage (IVH) is a type of ventricular bleeding that results in significant morbidity and mortality. Multiple studies have investigated the use of urokinase in IVH treatment. The use of urokinase may lead to higher rates of hematoma resolution and lower mortality rates. However, further studies are required to determine efficacy of urokinase administration. This study examined the association between urokinase use, IVH volume reduction, and clinical outcomes. In total, 94 adult patients with hypertensive intracerebral hemorrhage with ventricular extension or primary IVH were enrolled between 2015 and 2021. Participants were categorized into two groups: "EVD combined with fibrinolysis" and "EVD only." The primary objective was to assess the reduction of IVH severity. Additionally, the study evaluated the functional outcomes and shunt dependency rate as secondary outcomes. Non-contrast computed tomography scans were obtained to measure the severity of IVH using the mGRAEB score. The main outcomes were the association among urokinase administration, reduced IVH severity, and functional outcomes. There were no significant differences in the reduction rate of mGRAEB scores within a 7-day period (-50.0 [-64.4 to -32.5] % vs -44.2 [-59.3 to -7.9] %; p = 0.489). In addition, investigation of the third and fourth ventricles showed similar findings between the two groups. Urokinase treatment was not associated with significant differences in the modified Rankin Scale (5.0 (4.0-5.0) vs. 4.5 (4.0-5.0), p = 0.674) or shunt dependency rate (33.3% vs 39.3%, p = 0.58). This study found that intraventricular urokinase use in patients with IVH was not associated with reduced IVH severity. In addition, urokinase use was not associated with better functional outcomes or minor shunt dependency rates.

Fractalkine Enhances Hematoma Resolution and Improves Neurological Function via CX3CR1/AMPK/PPARγ Pathway After GMH.

Hematoma clearance has been a proposed therapeutic strategy for hemorrhagic stroke. This study investigated the impact of CX3CR1 (CX3C chemokine receptor 1) activation mediated by r-FKN (recombinant fractalkine) on hematoma resolution, neuroinflammation, and the underlying mechanisms involving AMPK (AMP-activated protein kinase)/PPARγ (peroxisome proliferator-activated receptor gamma) pathway after experimental germinal matrix hemorrhage (GMH). A total of 313 postnatal day 7 Sprague Dawley rat pups were used. GMH was induced using bacterial collagenase by a stereotactically guided infusion. r-FKN was administered intranasally at 1, 25, and 49 hours after GMH for short-term neurological evaluation. Long-term neurobehavioral tests (water maze, rotarod, and foot-fault test) were performed 24 to 28 days after GMH with the treatment of r-FKN once daily for 7 days. To elucidate the underlying mechanism, CX3CR1 CRISPR, or selective CX3CR1 inhibitor AZD8797, was administered intracerebroventricularly 24 hours preinduction of GMH. Selective inhibition of AMPK/PPARγ signaling in microglia via intracerebroventricularly delivery of liposome-encapsulated specific AMPK (Lipo-Dorsomorphin), PPARγ (Lipo-GW9662) inhibitor. Western blot, Immunofluorescence staining, Nissl staining, Hemoglobin assay, and ELISA assay were performed. The brain expression of FKN and CX3CR1 were elevated after GMH. FKN was expressed on both neurons and microglia, whereas CX3CR1 was mainly expressed on microglia after GMH. Intranasal administration of r-FKN improved the short- and long-term neurobehavioral deficits and promoted M2 microglia polarization, thereby attenuating neuroinflammation and enhancing hematoma clearance, which was accompanied by an increased ratio of p-AMPK (phosphorylation of AMPK)/AMPK, Nrf2 (nuclear factor erythroid 2-related factor 2), PPARγ, CD36 (cluster of differentiation 36), CD163 (hemoglobin scavenger receptor), CD206 (the mannose receptor), and IL (interleukin)-10 expression, and decreased CD68 (cluster of differentiation 68), IL-1β, and TNF (tumor necrosis factor) α expression. The administration of CX3CR1 CRISPR or CX3CR1 inhibitor (AZD8797) abolished the protective effect of FKN. Furthermore, selective inhibition of microglial AMPK/PPARγ signaling abrogated the anti-inflammation effects of r-FKN after GMH. CX3CR1 activation by r-FKN promoted hematoma resolution, attenuated neuroinflammation, and neurological deficits partially through the AMPK/PPARγ signaling pathway, which promoted M1/M2 microglial polarization. Activating CX3CR1 by r-FKN may provide a promising therapeutic approach for treating patients with GMH.

Role of N-formyl peptide receptor 2 in germinal matrix hemorrhage: an intrinsic review of a hematoma resolving pathway.

Germinal matrix hemorrhage is one of the leading causes of morbidity, mortality, and acquired infantile hydrocephalus in preterm infants in the United States, with little progress made in its clinical management. Blood clots have been shown to elicit secondary brain injury after germinal matrix hemorrhage, by disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage causing post-hemorrhagic hydrocephalus development. Current evidence suggests that rapid hematoma resolution is necessary to improve neurological outcomes after hemorrhagic stroke. Various articles have demonstrated the beneficial effects of stimulating the polarization of microglia cells into the M2 phenotype, as it has been suggested that they play an essential role in the rapid phagocytosis of the blood clot after hemorrhagic models of stroke. N-formyl peptide receptor 2 (FPR2), a G-protein-coupled receptor, has been shown to be neuroprotective after stroke. FPR2 activation has been associated with the upregulation of phagocytic macrophage clearance, yet its mechanism has not been fully explored. Recent literature suggests that FPR2 may play a role in the stimulation of scavenger receptor CD36. Scavenger receptor CD36 plays a vital role in microglia phagocytic blood clot clearance after germinal matrix hemorrhage. FPR2 has been shown to phosphorylate extracellular-signal-regulated kinase 1/2 (ERK1/2), which then promotes the transcription of the dual-specificity protein phosphatase 1 (DUSP1) gene. In this review, we present an intrinsic outline of the main components involved in FPR2 stimulation and hematoma resolution after germinal matrix hemorrhage.

Recruitment of regulatory T cells with rCCL17 promotes M2 microglia/macrophage polarization through TGFβ/TGFβR/Smad2/3 pathway in a mouse model of intracerebral hemorrhage

AimsIntracerebral hemorrhage (ICH) is a severe neurological condition with high mortality and morbidity. Microglia activation and peripheral inflammatory cells infiltration play an important role in ICH prognosis. Previous studies demonstrated that regulatory T cells (Tregs) ameliorated neuroinflammation following experimental ICH. However, the molecular mechanism underlying such effects of Tregs remains unclear. The objective was to examine how Tregs recruitment induced by recombinant CC chemokine ligand 17 (rCCL17) influences microglia/macrophage polarization in an intrastriatal autologous blood injection ICH animal model, and to determine if TGFβ/TGFβ-R/Smad2/3 pathway was involved. Methods380 adult CD1 mice (male, eight weeks old) were subjected to sham surgery or autologous blood injection induced ICH. A CD25-specific mouse antibody or isotype control mAb was injected intraventricular (i.c.v) 48 h prior to ICH induction to deplete Tregs. rCCL17, a CC chemokine receptor 4 (CCR4) ligand, was delivered intranasally at 1 h post-ICH. SB431542, a specific inhibitor of TGF-β was administered intraperitoneally 1 h before ICH induction. Following the ICH, neurobehavioral testing, brain edema, hematoma volume, hemoglobin content, western blotting, double immunofluorescence labeling, and immunohistochemistry were performed. ResultsEndogenous expressions of CCL17, Tregs marker Foxp3, and the number of Tregs in perihematomal region increased following ICH. Tregs depletion with a CD25 antibody aggravated neurological deficits and brain edema, increased inflammatory cytokines, neutrophil infiltration, oxidative stress, and reduced the rate of hematoma resolution in ICH mice. rCCL17 treatment increased the number of Tregs in the brain, ameliorated neurological deficits and brain edema after ICH, and promoted microglia/macrophage polarization toward M2 phenotype which was reversed with CD25 antibody. Moreover, rCCL17 increased the expressions of brain TGF-β/phosphorylated-Smad2/3 which was abrogated with the selective TGFβ inhibitor SB431542. ConclusionsrCCL17-mediated Tregs recruitment may be a potential therapeutic strategy to promote M2 microglia/macrophages polarization and alleviate early brain injury following ICH.