Current Neurovascular Research - Volume 22, Issue 3, 2025

Although ischemic stroke is associated with complex changes in the autonomic nervous system, the circadian patterns of heart rate (HR) and heart rate variability (HRV) in wake-up stroke (WUS) remain poorly understood. This study compared 24-hour heart rate and HRV patterns between patients with and without WUS.

This retrospective observational case-control study involved 104 patients with acute ischemic stroke (9 WUS, 95 non-WUS). HRV analysis was performed using a 14-day continuous electrocardiography patch monitor. Time- and frequency-domain HRV metrics were calculated, and 24-hour differences were assessed using generalized additive mixed models (GAMMs), adjusting for confounders.

WUS patients had significantly higher HRs (80.60 ± 12.49 vs. 73.22 ± 14.49 beats per minute, P < 0.001) and lower HRV-measured by SDNN (28.06 ± 21.68 vs. 39.70 ± 25.73 milliseconds, P < 0.001), RMSSD (15.78 ± 12.49 vs. 22.16 ± 19.22 milliseconds, P < 0.001), and pNN50 (1.03% ± 2.78% vs. 2.61% ± 5.15%, P < 0.001)-than non-WUS patients. GAMMs indicated that patients with WUS experienced significant autonomic dysregulation, characterized by higher HRs, lower HRV, and altered circadian rhythms compared to those with non-WUS. These differences were particularly evident during the early morning hours.

WUS patients exhibited distinct 24-hour HR and HRV profiles, characterized by higher HRs and reduced autonomic variability compared to non-WUS patients. These differences align with patterns typically associated with lower parasympathetic activity rather than elevated sympathetic tone.

WUS is associated with impaired autonomic regulation and disrupted circadian patterns of HR and HRV.

Hemorrhagic stroke is a severe disease that endangers human life and well-being, with unclear pathogenesis. Recent studies have found an association between the immune system and hemorrhagic stroke, but the causal relationship between them remains unclear. We aim to elucidate the causal relationships between immune cell traits and hemorrhagic stroke using Mendelian randomization (MR).

We collected genome-wide association studies (GWAS) summary statistics for 731 immune cell traits as exposures, and GWAS data for hemorrhagic stroke outcomes, including intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and cerebral aneurysm (non-ruptured) (CA), from the FinnGen Consortium's R10 dataset. Five methods were employed to evaluate the causal relationships, with the primary method being the inverse-variance weighted (IVW) method. Sensitivity analyses were carried out to enhance the robustness. Subsequently, we performed multivariate MR analyses, including confounding variables. Additionally, reverse MR analyses were carried out. Ultimately, we conducted pathway and functional enrichment analyses.

After univariate and multivariate MR analyses, we identified that the higher counts of herpesvirus entry mediator (HVEM) on effector memory (EM) CD4+ cells (OR=0.954, 95%CI:0.925-0.984, P=0.003, PFDR=0.120) were a protective factor for SAH, and the counts of forward scatter area (FSC-A) on plasmacytoid dendritic cells (DC) (OR=1.059, 95%CI:1.023-1.095, P=0.001, PFDR=0.066) were associated with an increased risk of CA. The reverse MR indicated that CA could significantly increase the effector memory (EM) DN (CD4-CD8-) AC counts. No significant pleiotropy or heterogeneity was calculated in the MR analyses. SNP annotation and enrichment analyses suggested possible mechanisms by which immune cells affect hemorrhagic stroke.

The involvement of immune cells in the neuroinflammatory responses has been demonstrated in previous studies. Among the immune cell traits with a significant causal relationship to hemorrhagic stroke, higher levels of HVEM on EM CD4+ cells may inhibit further inflammatory progress by binding to corresponding receptors, thereby exerting a protective effect against SAH. Alterations in FSC-A values (a flow cytometry measure of cell size) of plasmacytoid dendritic cells may contribute to atherosclerosis through cascading reactions that ultimately lead to CA. In addition, based on existing studies, other immune cell traits and related pathways identified in this study may contribute to the prevention and treatment of hemorrhagic stroke, providing a reference for future research. Finally, this study has some limitations, including population specificity, the use of a relatively lenient significance threshold (P < 1 × 10^-5), and potential bias from weak instrumental variables and pleiotropy.

This study demonstrated the causal relationships between immune cell traits and hemorrhagic stroke, laying the foundation for understanding the underlying mechanisms.

This study aims to investigate the effect of the serum Total Cholesterol (TC) to High-Density Lipoprotein cholesterol (HDL) ratio (T/H ratio) on Hemorrhagic Transformation (HT) after Intravenous Thrombolysis (IVT) in patients with Acute Cerebral Infarction (ACI).

Patients with ACI who received alteplase were enrolled. Subgroups were classified based on the occurrence of hemorrhagic transformation (HT) after intravenous thrombolysis (IVT), whether tirofiban was coadministered, and their 90-day prognosis. The primary observation indicators were HT and the 90-day prognosis. Single-factor and multi-factor analyses were performed to identify independent predictors of HT and prognosis.

Age, TC, and HDL were identified as risk factors for ACI. The T/H ratio and HDL were statistically significant in relation to HT (p < 0.05). A correlation was observed between the T/H ratio and HT, with HT more likely to occur when the T/H ratio was greater than or equal to 3.25. The use of tirofiban after IVT did not increase the risk of HT. Significant differences were observed in HT, type of HT, age, hypertension, baseline National Institutes of Health Stroke Scale (NIHSS) score, platelet volume distribution width, TC, D-dimer, and fibrinogen degradation products between groups with different prognoses.

The T/H ratio was statistically associated with HT-ACI and predicted HT-ACI to some extent. However, the study had two limitations: the small sample size and the assessment of prognosis through follow-up phone calls, which affected the final results.

Patients with ACI undergoing IVT who had higher baseline NIHSS scores, lower TC, higher HDL, and a higher T/H ratio were at increased risk of HT, which was also associated with long-term outcomes. The T/H ratio may be a valuable predictor of HT following IVT.

This study investigated the neuroprotective mechanisms of ischemic postconditioning (IPostC) in ischemic stroke, focusing on ferroptosis and the regulatory role of the ferroptosis-related gene NADPH oxidase 4 (NOX4).

Male C57BL/6 mice underwent 45-minute middle cerebral artery occlusion (MCAO), followed by IPostC (three 15s/30s ischemia/reperfusion cycles after initial 2-minute reperfusion). RNA sequencing, combined with the least absolute shrinkage and selection operator (LASSO) and random forest machine learning, quantitative real-time PCR (qRT-PCR), infarct size measurement, and neurological tests, was used to identify ferroptosis-related genes and validate their roles in IPostC-induced neuroprotection.

RNA sequencing revealed that 42 ferroptosis-associated differentially expressed genes underlie the neuroprotective effects of IPostC. Among them, NOX4 emerged as a central pathogenic regulator through LASSO and random forest machine learning analyses. IPostC reduced cerebral infarct size and improved foot-fault rate compared to MCAO mice. Notably, the ferroptosis inducer Erastin abolished the protective effects of IPostC. qRT-PCR validation revealed that IPostC downregulated NOX4 mRNA expression compared to MCAO controls, while Erastin upregulated NOX4 expression. In addition, pharmacological inhibition of NOX4 with GLX351322 reduced its mRNA expression, decreased infarct size, and improved neurological function, further confirming its critical role in mediating ferroptosis-driven brain injury after ischemic stroke.

The inhibition of ferroptosis-associated gene NOX4 by IPostC may be a novel mechanism for treating ischemic stroke.

Our study indicates that IPostC attenuates cerebral ischemic injury by suppressing ferroptosis-associated gene NOX4.

The objective of this study was to investigate the effects of 3',4'-dihydroxyflavonol (DiOHF) on oxidative and antioxidant systems in kidney tissue and on renal function as distant organ damage following brain ischemia-reperfusion.

This study was conducted on 28 male Wistar-Albino rats, which were divided into four groups: Control, Sham, Ischemia-Reperfusion (I/R), and Ischemia-Reperfusion + DiOHF. Kidney tissue samples were collected to analyze malondialdehyde (MDA) and glutathione (GSH) levels. Additionally, concentrations of electrolytes (Ca, Cl, Na, K, and P), as well as urea, uric acid, creatinine, and urinary microprotein levels, were measured.

Brain ischemia-reperfusion led to increased malondialdehyde (MDA) levels in both the kidney medulla and cortex, indicating oxidative stress in these distant organs, while glutathione (GSH) levels were suppressed. Additionally, ischemia-reperfusion caused elevations in blood and urine concentrations of urea, uric acid, creatinine, and urinary microproteins.

This experimental model significantly elevated urea, uric acid, and creatinine levels, key indicators of kidney function, and similarly increased urinary microprotein loss. While our study demonstrates the detrimental effects of focal brain ischemia-reperfusion on kidney function as a distant organ, further research is needed to investigate its impact on other organs to gain a more comprehensive understanding of distant organ damage.

Results from this experimental model indicate that cerebral ischemia-reperfusion in rats suppresses the antioxidant system and increases oxidative stress in kidney tissue, leading to impaired renal function. However, a 1-week DiOHF treatment mitigated this damage by enhancing the antioxidant defense system.

Olfactory epithelium (OE) comprises diverse cell types, including olfactory sensory neurons (OSNs), supporting cells, and basal stem cells. While interleukin (IL)-4 is a key mediator in type 2 inflammation, its regulatory role in OE remains unclear. The current study aimed to explore the role of IL-4 in olfactory epithelial cells.

Using an olfactory epithelial organoid model, the impacts of IL-4 on different cell types were assessed by performing qPCR, immunofluorescence staining, and EdU incorporation assays. Calcium imaging was performed to assess the influence of IL-4 on OSNs, while Alcian Blue-Periodic Acid-Schiff (AB-PAS) staining was used to analyze mucin secretion in the organoids.

IL-4 significantly promoted the proliferation of globular basal cells (GBCs) in basal cells, induced homeostasis of mature OSNs, and maintained the normal function of OE. However, IL-4 notably downregulated GAP43 expression in immature OSNs. Additionally, IL-4 enhanced mucin secretion in the OE.

This study found that IL-4 promoted the differentiation of OE cells by stimulating the proliferation of GBCs and enhancing mucin secretion, while maintaining the normal function of mature olfactory neurons. Further clinical studies are needed to validate these results.

This study revealed the role of IL-4 in OE, providing novel insights into the mechanisms of IL-4 in inflammatory conditions.

Epilepsy is a neurological disorder characterized by recurrent seizures that can cause long-standing disturbance of normal brain function. It may adversely affect academic performance, behavior, emotional adjustment, social adaptability, and overall development in children. Neurotrophic factors and inflammatory markers are believed to play key roles in the pathogenesis of epilepsy. This study evaluated the effect of levetiracetam monotherapy and its combination with phenytoin on serum brain-derived neurotrophic factor (BDNF) levels, Interleukin-2 (IL-2) levels, and social adaptability/development in children with epilepsy.

Children with epilepsy, aged 1 to 12 years, were given levetiracetam monotherapy (n=30) and combination therapy of levetiracetam and phenytoin (n=30) for 20 weeks. Healthy controls (n=30) were also included. Serum BDNF and IL-2 levels were assessed at baseline and 20 weeks, along with social adaptability and development, using the Vineland Social Maturity Scale (VSMS) and Developmental Screening Test (DST) scores, respectively.

Pretreatment, serum BDNF and IL-2 levels were significantly (p <0.001) lower and higher respectively, in both treatment groups compared to controls. After 20 weeks, BDNF and IL-2 levels were significantly (p <0.001) increased and decreased, respectively, in the monotherapy group and combination therapy group. VSMS and DST scores improved significantly (p <0.001).

The findings suggest that levetiracetam and its combination with phenytoin modulate neurotrophic and inflammatory pathways in pediatric epilepsy, with parallel improvements in social and developmental outcomes.

Levetiracetam monotherapy and its combination therapy with phenytoin increased serum BDNF levels, decreased IL-2 levels, and improved VSMS and DST scores in pediatric epilepsy patients, suggesting that these treatments influence epileptogenesis.