Translational Stroke Research最新文献

Acute ischemic stroke (AIS) is a major cause of disability and mortality worldwide. While antiplatelet therapy is standard for secondary prevention, many patients still experience early neurological deterioration (END). Argatroban, a direct thrombin inhibitor, can potentially limit thrombus progression and improve AIS's functional outcomes. This meta-analysis assessed the efficacy and safety of argatroban in combination with single (SAPT) or dual antiplatelet therapy (DAPT) compared to antiplatelets alone. Following PRISMA guidelines, a systematic search of PubMed, Scopus, and Web of Science was conducted until January 2025. Randomized controlled trials (RCTs) and cohort studies evaluating argatroban plus antiplatelets versus antiplatelets alone in AIS patients were included. The primary outcome was a 90-day modified Rankin Score (mRS) of 0-2. Secondary outcomes included mRS 0-1 and mRS 3-5 at 90 days, END, and National Institutes of Health Stroke Scale (NIHSS) improvement, stroke recurrence, intracranial hemorrhage (ICH), symptomatic intracranial hemorrhage (sICH), and mortality. We used the mean difference (MD) for continuous variables and odds ratio (OR) for dichotomous ones at 95% confidence intervals (CI) and a P-value of 0.05. A total of 14 studies (four RCTs and 10 cohort studies) were included. Compared to antiplatelets alone, argatroban significantly improved functional outcomes, increasing the incidence of mRS 0-2 (OR = 1.36 [95%CI: 1.05, 1.76, P = 0.02]) and mRS 0-1 (OR = 1.54 [95%CI: 1.08, 2.2, P = 0.02]) while reducing END (OR = 0.42 [95%CI: 0.21, 0.85, P = 0.02]). Argatroban was also associated with greater NIHSS score improvement (MD =  - 0.52 [95%CI: - 0.89, - 0.15, P = 0.005]). No significant differences were observed in mRS 3-5, stroke recurrence, ICH, sICH, or mortality. Subgroup analysis indicated that argatroban combined with DAPT showed the greatest benefits. Argatroban combined with antiplatelet therapy improves functional recovery and reduces END without increasing bleeding risks. These findings support its use, particularly with DAPT, in mild to moderate AIS management. Further large-scale RCTs are needed to optimize dosing strategies and patient selection.

Intracranial aneurysms (IAs) are a major cause of spontaneous subarachnoid hemorrhage (SAH) and are associated with high morbidity and mortality. Current IA rodent models often exhibit low rupture rates and limited imaging capabilities, restricting their translational utility. This study introduces a modified elastase-based rat model that incorporates angiographic imaging to overcome these challenges. IAs were induced in 7-week-old female Sprague-Dawley rats using a combination of surgical and pharmacological interventions, including carotid artery and renal artery ligation, bilateral ovariectomy, high-salt diet, and two elastase injections into the basal cistern. Digital subtraction angiography (DSA) was employed to assess aneurysm formation and rupture rate. Histological and immunohistochemical analyses were conducted to characterize aneurysm morphology and the inflammatory response. The modified model achieved a high rate of IA formation (85%) and rupture (60%) within 28 days. DSA enabled visualization of vessel tortuosity and flow dynamics, features relevant to human IA development, which often occurs in areas subjected to hemodynamic stress, and the tortuosity of intracranial vessels affects their rupture ^[1]. Histological analysis indicated structural degradation of the aneurysm wall, while immunohistochemistry showed neutrophil infiltration, potentially implicating inflammation in IA rupture. This improved IA model offers a reliable method for inducing and visualizing IAs with a high rupture rate, making it a valuable tool for studying the pathophysiology and therapeutic interventions of IAs. Enhanced by DSA, this model has the potential to advance therapeutic research by enabling the real-time monitoring of aneurysm development and rupture.

Stroke is a prevalent age-related disease globally, contributing significantly to neurological dysfunction, disability, and mortality rates. Despite its substantial healthcare burden, effective therapies remain limited. Na/K-ATPase (NKA), beyond its canonical role in ion homeostasis, emerges as a pivotal player in oxidative stress induction, implicating its potential as a therapeutic target. Here, we investigate the efficacy of the semi-synthetic cardiotonic steroid gamma-benzylidene digoxin-15 (BD-15) in ameliorating brain ischemia-induced damage. A total of 44 male Wistar albino rats were randomly assigned to four groups (n = 11/group). The animals were subjected to experimental brain ischemia induction and treated with BD-15. Behavioral assessments revealed a significant improvement in mobility and exploration in BD-15-treated rats compared to brain ischemia alone (P < 0.05). Histological analysis suggested a reduction in brain damage in BD-15-treated rats. Moreover, BD-15 administration attenuated oxidative stress, evidenced by decreased thiobarbituric acid reactive substances levels (TBARS) in the hippocampus and sensory-motor cortex in brain ischemia rats (P < 0.05). Additionally, BD-15 treatment mitigated changes in lipid composition, possibly via modulation of membrane integrity. BD-15 also significantly restored ionic homeostasis in brain ischemia rats, improving the activities of NKA, Ca²⁺-ATPase, Sarcoendoplasmic Reticulum Calcium ATPase, and Mg²⁺-ATPase activities in the hippocampus and sensory-motor cortex (P < 0.05). Notably, acetylcholinesterase activity in brain ischemia rats was improved after BD-15 treatment (P < 0.05), suggesting additional benefits in maintaining neurotransmission following ischemic injury. These findings suggest a multifaceted neuroprotective mechanism of BD-15 in brain ischemia pathology. Our results propose BD-15 as a promising therapeutic strategy for mitigating ischemia-induced neurotoxicity. Further clinical studies are necessary to validate these findings and explore the translational potential of BD-15 in human stroke management.

Stroke-associated pneumonia (SAP) is the most significant acute ischemic stroke (AIS) comorbidity. This investigation aimed to explore the relationship between gut microbiome composition and SAP risk in patients with moderate-to-severe AIS and to develop a robust and accessible SAP risk-prediction model for this population. This prospective study included AIS patients with an NIHSS score ≥ 9 within 48 h of onset who were admitted to the First Affiliated Hospital of Wenzhou Medical University. Rectal swabs and sputum samples were collected for 16S rRNA gene sequencing and analyzed via QIIME to evaluate microbial composition. Blood samples were subjected to untargeted metabolomics analysis via liquid chromatography‒mass spectrometry (LC‒MS). Logistic and Cox regression analyses were conducted (α = 0.05). Fifty of 104 AIS patients (48.1%) developed SAP. Microbiota abundances significantly differed between groups. Logistic regression analysis revealed that Finegoldia protected against SAP (OR 0.710, 95% CI: 0.533 - 0.946, p = 0.019), whereas Lactobacillus (OR 1.347, 95% CI: 1.015 - 1.789, p = 0.039) increased SAP risk. An improved SAP prediction model combining the A²DS² score with seven taxa yielded an AUC of 0.746 (95% CI: 0.650 - 0.841, p < 0.001). Cox regression analysis revealed that genus Clostridium (HR 1.618, 95% CI: 1.241 - 2.110, p < 0.001) was an independent risk factor for mortality, whereas genus Streptococcus (HR 0.751, 95% CI: 0.589 - 0.958, p = 0.021) was a protective factor. Our findings suggest that combining clinical indicators, gut microbiota, and blood metabolites enhances SAP prediction. Furthermore, microorganisms can potentially serve as prognostic markers and therapeutic targets for SAP in the future.

Laboratory ratios such as the neutrophil-to-lymphocyte, platelet-to-lymphocyte, and stress hyperglycemia ratios have been widely studied as prognostic markers in stroke. Despite hundreds of reports and multiple meta-analyses, these indices have shown modest effect sizes and have not influenced clinical guidelines or trial design. This commentary argues that such ratios serve as surrogates of systemic physiology rather than actionable prognostic tools, highlighting the gap between statistical association and clinical translation.

Intracerebral hemorrhage (ICH) along with aggravating factors, such as edema, can raise intracranial pressure (ICP) to pathological levels. Diversion of some cerebrospinal fluid (CSF) and venous blood out of the cranium can limit ICP rises while maintaining cerebral perfusion pressure. Brain tissue itself is widely considered immutable in volume but prone to distortion (e.g., midline shift). However, distal brain regions shrink acutely following ICH in rodents. Tissue contraction arises from cell shrinkage and increased packing density. This "tissue compliance" is hypothesized to be an additional mechanism to limit ICP rises. Here, we examined whether and by how much parenchyma volume reduction occurs in ICH patients. We conducted a retrospective analysis on computed tomography (CT) scans of 96 ICH patients (average age 63.8 years old, 55% male) with an average hematoma volume of 32.4 and 35.3 mL at the first and second scan (separated by ~ 23 h), respectively. Hematoma growth (any absolute increase) occurred in 44% of patients, with a minimal but significant growth of the hematoma of 2.9 mL on average across all patients (p = 0.028). As hypothesized, the contralateral hemisphere volume was significantly reduced by 12.7 mL (p < 0.0001) between scans. This was unrelated to midline shift (R² = 0.012, p = 0.21), which averaged 2.3 mm. These findings suggest that distal parenchymal shrinkage may be a major compliance mechanism after ICH; the implications for ICP and brain function merit further study.

Intracerebral hemorrhage (ICH) is characterized by the rupture of blood vessels, allowing components from peripheral circulation to infiltrate the brain and impair central immune functions. This study employs non-targeted metabolomics to compare cerebrospinal fluid (CSF) metabolites between acute-phase and recovery-phase of ICH, aiming to identify metabolites associated with ICH central inflammation. CSF and plasma samples were collected from a retrospective observational cohort of participants with ICH (n = 38). Additionally, we obtained CSF samples from patients who underwent lower limb surgery due to accidental injuries, serving as healthy controls (n = 12). Non-targeted metabolomics analysis was performed, and inflammatory factors in the CSF were measured. The association between these metabolites and inflammation in the CSF was validated using a collagenase-induced ICH mouse model and microglial cultures in vitro. Our results demonstrate that the levels of certain metabolites in the cerebrospinal fluid of ICH patients changed significantly from the acute phase to the recovery phase (P < 0.05, VIP > 1). Furthermore, the concentration of inflammatory factors in the acute-phase CSF was significantly higher compared to both the recovery phase of ICH and healthy control levels. Correlation analyses of inflammatory factors and the patients' CSF metabolites revealed several metabolites associated with central inflammation. Notably, kynurenic acid (Kyna) exhibited a positive correlation with central inflammation and a negative correlation with the Glasgow Coma Scale (GCS). In the collagenase-induced ICH mouse model, elevated levels of Kyna were also associated with increased inflammation in the CSF. Additionally, in vitro studies demonstrated that Kyna regulates inflammatory cytokines by activating microglia. Our study highlights a significant relationship between metabolites in the CSF of ICH patients and central inflammation. Specifically, Kyna promotes inflammation by activating microglia, suggesting its potential as a promising target for therapeutic intervention in ICH central inflammation. Registration: 2023-KY-155-02.

Microcirculatory dysfunction is an important pathophysiology mechanism of early brain injury after aneurysmal subarachnoid hemorrhage (aSAH), which contributes to poor outcomes. The study was performed in Beijing Tiantan Hospital from October 2020 to July 2023. Patients with aSAH who underwent computed tomographic perfusion (CTP) within 24 h after ictus were enrolled prospectively. The peak time of arterial inflow (PTA), peak time of venous outflow (PTV), total venous outflow time (TVT), and difference value of arteriovenous peak time (DV) were collected from the time-density curve of CTP. Primary outcome was 3-month unfavorable functional outcome (modified Rankin Scale score of 4-6). Secondary outcomes included 3-month all-cause death and delayed cerebral ischemia. Multivariable logistic regression analysis and restricted cubic splines were performed to explore the relationship between cerebral hemodynamic parameters and outcomes. We also assessed the prognostic performance of incorporating hemodynamic parameters into previous nomogram models for 3-month poor clinical outcomes. A total of 612 patients were enrolled, among whom the mean age was 56.9 ± 12.3 years old and 391 (63.9%) were female. On multivariable analysis, prolonged TVT could significantly predict 3-month poor functional outcome (adjusted OR 1.074, 95%CI 1.013-1.139), while prolonged PTA was an independent predictor of 3-month all-cause death (adjusted OR 1.293, 95%CI 1.099-1.521). The addition of TVT or PTA to previous nomogram models led to improvements in C-statistics, net reclassification (NRI), and integrated discrimination improvement (IDI). Our study underscores the vital role of arterial inflow and venous outflow in sustaining microcirculation during the acute phase after aSAH, thereby offering new directions for future investigations into therapeutic targets.

Perihematomal edema (PHE) significantly aggravates secondary brain injury in patients with intracerebral hemorrhage (ICH), yet its detailed mechanisms remain elusive. Neutrophil extracellular traps (NETs) are known to exacerbate neurological deficits and worsen outcomes after stroke. This study explores the potential role of NETs in the pathogenesis of brain edema following ICH. The rat ICH model was created, immunofluorescence and Western blot were used to examine neutrophil accumulation, NET markers citrullinated histone H3 (CitH3) and myeloperoxidase (MPO), tight junction proteins (ZO-1 and Occludin), Aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), and ERK phosphorylation (p-ERK) in brain tissues surrounding the hematoma. TUNEL staining and behavioral tests were employed to evaluate neuronal apoptosis and neurological dysfunction, while blood-brain barrier (BBB) permeability and brain edema were also measured by Evans blue and brain water content. Furthermore, the molecular mechanisms related to NETs-induced PHE were investigated using NETs, ERK, MMP-9 and AQP4 regulators, respectively. Ly6G⁺ neutrophils surrounding the hematoma developed NETs within 3 days post-ICH. NETs decreased tight junction proteins, destroyed BBB integrity, promoted brain edema, increased neuronal apoptosis, and exacerbated neurological deficits. Conversely, inhibition of NETs mitigated PHE, reduced neuronal apoptosis, and improved neurological functions. Mechanistically, NET-induced PHE was originated from impairment of BBB tight junction via ERK/MMP9 pathway, coupled with ERK-mediated AQP4 downregulation in perihematomal regions. These findings elucidated the effects of NETs on PHE, which offered promising insights for targeting NETs to relieve brain edema and secondary brain injury post-ICH.