Current Neurovascular Research - Volume 21, Issue 4, 2024

Nearly half of Acute Ischemic Stroke (AIS) patients failed to achieve favorable outcomes despite successful reperfusion treatment. This phenomenon is referred to as Futile Recanalization (FR). Screening patients at risk of FR is vital for stroke management. Previous studies reported the diagnostic value of alkaline phosphatase (ALP) levels in certain aspects of stroke prognosis. However, the association between serum ALP level and FR among AIS patients treated with thrombectomy remained unclear.

We screened stroke patients who underwent thrombectomy at our center from January 2017 to June 2021, and those who achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction score=3) were ultimately analyzed. Demographic information, vascular risk factors, and laboratory test results were collected at admission. The 3-month unfavorable outcome was defined as a modified Rankin Scale score of 3 to 6. The effect of ALP levels on FR was investigated with a logistic regression model.

Of 788 patients who underwent thrombectomy, 277 achieved successful reperfusion. Among them, 142 patients (51.3%) failed to realize favorable outcomes at 3 months. After adjusting for confounding variables, higher ALP levels (p =0.002) at admission were independently associated with unfavorable outcomes at three months. Adding ALP values to conventional risk factors improved the performance of prediction models for FR.

The current study found that the serum ALP levels at admission emerged as a potential biomarker for futile reperfusion in stroke patients undergoing thrombectomy. Further studies are warranted to confirm the clinical applicability of ALP level for futile recanalization prediction.

Increasing evidence of circadian biology may influence the physiopathologic mechanism, progression, and recovery of stroke. However, few data have shown about circadian rhythm on futile recanalization (FR) in patients treated with endovascular treatment (EVT).

From 2017 to 2021, an observational cohort of acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) underwent EVT was conducted. FR was defined as the failure to achieve functional independence in patients at 90 days after EVT, although the occluded vessels reached a recanalization. The effect of circadian rhythm on FR was investigated using the logistic regression model.

Of 783 patients, there were 149 patients who had stroke onset between 23:00-6:59, 318 patients between 7:00-14:59, and 316 patients between 15:00-22:59. Patients suffered from stroke during 15:00-22:59 had shorter OTP (p =0.001) time, shorter OTR (p<0.001) time, higher rate of intravenous thrombolysis (p =0.001) than groups of other time intervals. The rate of FR post-EVT in patients who had a stroke between 15:00-22:59 was significantly higher than in those with stroke onset between 23:00-6:59 (p =0.017). After adjusting for confounding factors, the time of stroke occurring during 15:00-22:59 (adjusted OR [aOR], 1.652; 95%CI, 1.024-2.666, p =0.04) was an independent predictor of FR.

Circadian rhythm can directly or indirectly affect the occurrence, development, and prognosis of AIS. More studies may be needed in the future to validate the results of our study and to explore the potential mechanisms behind the effects of circadian rhythms on FR.

Parkinson's disease is an illness marked by a gradual mitigation of dopamine neurons within the substantia nigra, which eventually leads to a deficiency of dopamine that further gives rise to mobility as well as cognitive impairments. Through long-established traditions, a wide array of Traditional Chinese Medicines (TCM) have undergone testing and are employed to avoid neurodegenerative disorders. Plumbagin is the primary active component of a medication called Baihua Dan or Plumbago zeylanica L., which is clinically used in China.

This study investigated plumbagin-induced alterations in a Parkinson's disease rat model instigated by subcutaneous rotenone injection.

Male rats were administered subcutaneous injections of rotenone at a dosage of 1.5 mg/kg, followed by the treatment with varying doses of plumbagin (10, 20, and 40 mg/kg) through the oral route. The rats underwent various motor ability tests, including the actophotometer, rotarod, open field, beam walk, gait evaluation, ability to grip, and catalepsy bar tests. Furthermore, the brain dopamine level was then estimated for the extracted tissues. Also, through molecular docking, the binding effectiveness of plumbagin was assessed for human MAO-B. After that, plumbagin was put through 100 ns of molecular dynamic simulations to examine the stability of its conformational binding to the target protein. Furthermore, ADMET tests were used to verify Plumbagin's druggability.

Plumbagin was found to alleviate rotenone-induced motor abnormalities and restore brain dopamine levels. Furthermore, plumbagin showed excellent interactions with MAO-B (monoamine oxidase-B) when compared with selegiline (a standard drug for Parkinson’s disease).

These findings underscore the potential therapeutic efficacy of plumbagin in mitigating behavioural deficits in rotenone-induced rodents. Considering this, plumbagin might be a feasible pharmacological strategy for the control of rotenone-triggered behavioural impairment in rats (in vivo), and it might display interesting interactions with MAO-B (in silico).

To explore the effect of baseline Systemic Inflammatory Response reflected by platelet-to-lymphocyte ratio (PLR) and pre-thrombectomy cerebral edema reflected by Net Water Uptake (NWU) on futile recanalization in patients with Acute Ischemic Stroke (AIS) after successful thrombectomy, and to investigate the potential mediating role of baseline cerebral edema.

134 Patients with anterior circulation ischemic stroke receiving successful thrombectomy were retrospectively studied. Their demographic and clinical characteristics were collected at admission, and the NWU was quantitatively calculated based on baseline computed tomography (CT). The predictive value of PLR for futile recanalization and the relationship between PLR, NWU, and futile recanalization using mediation analysis were explored. Patients were followed up for 90 days and were divided into a futile recanalization group and a favorable prognosis group [90-day modified Rankin Scale score of 0–2].

High baseline PLR, NWU, no first-pass reperfusion, and large baseline ischemic core volume were independent predictors of futile recanalization after successful thrombectomy in patients with AIS. Mediation analysis results indicate that PLR may partially mediate the occurrence of futile recanalization through NWU.

Baseline PLR and NWU were independent predictors of futile recanalization, and higher PLR and NWU values were associated with a higher likelihood of futile recanalization. The findings suggest that early cerebral edema reflected by a high NWU value may be a mediator of PLR-affecting prognosis.

Aloe-emodin (AE), a monomer derived from traditional Chinese medicine, has demonstrated remarkable efficacy in the clinical management of cognitive disorders. Ferroptosis (FPT), a specialized form of programmed cell death, plays a critical role in the pathological progression of various cognitive diseases.

This study explored the therapeutic potential of AE in a rat model of Wilson's disease cognitive impairments (WDCI) and examined whether these effects are mediated through the silencing information regulator 1 (SIRT1)-regulated FPT signaling pathway. Employing techniques, such as the Morris water maze (MWM), Hematoxylin & eosin (H&E) staining, Transmission electron microscopy (TEM), Immunofluorescence (IF), assessments of oxidative stress markers, and measurements of FPT-related protein levels, we evaluated the extent of SIRT1-mediated FPT and the therapeutic efficacy of AE.

The findings from the WD copper-loaded rat model experiments revealed that MWM, H&E, TEM, and IF outcomes indicated AE's potential to promote the restoration of learning and memory functions, ameliorate hippocampal neuronal morphological damage, and preserve cell membrane integrity. Results from western blot (WB) and ELISA analyses demonstrated that AE markedly upregulated the expression of SIRT1, nuclear factor erythroid-2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SCL7A11), and glutathione peroxidase 4 (GPX4) proteins while simultaneously reversing the expression of oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), and reactive oxygen species (ROS). Consequently, we posit that AE may attenuate WD copper-loaded rat model hippocampal neuronal FPT by activating the SIRT1-mediated signaling pathway.

These findings suggested that AE mitigates WD copper-loaded rat model hippocampal neuronal damage through the activation of SIRT1-mediated FPT, thereby presenting a valuable candidate Chinese herbal monomer for the clinical treatment of WDCI.

Stroke, primarily known as ischemic stroke, is a leading cause of mortality and disability worldwide. Reperfusion after the ischemia stroke resolves is necessary for maintaining the health of brain tissues; however, it also induces inflammation and oxidative stress, resulting in brain injury. This study aimed to investigate the role of circ0001679 in the pathology of I/R (Ischemia/Reperfusion)-induced brain injury and explore its therapeutic potential for I/R injury.

The Oxygen-Glucose Deprivation/Re-oxygenation (OGD/R) model was employed in primary mouse astrocytes, and the Middle Cerebral Artery Occlusion (MCAO) model was established in mice to mimic ischemia-reperfusion-induced injury. Si-circ0001679, anti-miR-216, and TLR4 ORF-clone were transfected either in cells or mice to study the molecular mechanisms during I/R-induced injury. Inflammation and oxidative stress were monitored after treatment.

Upregulated gene expression of circ0001679 was noticed in both OGD/R-treated primary mouse astrocytes and MCAO-induced mouse brain tissue. Silencing circ0001679 reduced cellular damage, inflammation, and oxidative stress induced by OGD/R treatment. Knocking down of circ0001679 alone with either miR-216 inhibition or TLR4 overexpression increased the inflammation response and oxidative stress compared to circ0001679 silencing only. Moreover, inhibition of circ0001679 attenuated brain injury in MCAO-treated mice via reduced infarction, neuronal damage, apoptosis, inflammation, and oxidative stress.

This study unveiled a novel regulatory axis of circ0001679-miR-216-TLR4 in I/R-induced brain injury. Targeting circ0001679 may represent a promising therapeutic strategy for I/R-induced brain injury.

Ischemic stroke due to Large Vessel Occlusion (LVO) represents a critical and time-sensitive neurological emergency. Advancements in imaging technology and endovascular therapies have transformed the management of LVO. Nonetheless, thrombectomy failure diminishes the chances of patients achieving a favorable clinical outcome.

We aimed to determine the factors influencing recanalization failure in order to optimize thrombectomy therapy along with enhancing patient outcomes.

A retrospective analysis was performed employing consecutive LVO patients who underwent Endovascular Thrombectomy (EVT) in a tertiary comprehensive stroke center between January 2020 and June 2024. Recanalization failure (mTICI 0-2a) following thrombectomy was assessed using the Kolmogorov-Smirnov test, χ² test, Fisher’s exact test, and multivariable logistic regression to identify the related factors.

A total of 82 EVT patients were analyzed. The mean age was 58.20 years and 70.73% of the patients were male. The rate of recanalization failure was 61%. Multivariable logistic regression analysis with age-sex adjusted factors has revealed hypertension [aOR: 5.31 (95% CI: 1.23-22.77); p =0.025] and no IVT [aOR: 2.75 (95% CI: 1.06-7.14); p =0.037] to be independent predictors of recanalization failure in this study.

Hypertension and the absence of prior intravenous thrombolysis have been found to be significant contributing factors to the high rate of thrombectomy failure in large-vessel occlusion.

Electroacupuncture (EA) exerts a protective role in Blood-brain Barrier (BBB) damage after ischemic stroke, but whether this effect involves the regulation of the pericytes in vitro is unclear.

The in vitro BBB models were established with brain microvascular endothelial cells (BMECs) and pericytes, and the co-cultured cells were randomly divided into three groups: the control group, oxygen-glucose deprivation/reoxygenation (OGD/R) group and EA group. OGD/R was performed to simulate cerebral ischemia-reperfusion in vitro. EA serum was prepared by EA treatment at the “Renzhong” (GV26) and “Baihui” (GV20) acupoints in middle cerebral artery occlusion/reperfusion rats. Furthermore, the characteristics of BMECs and pericytes were identified with immunological staining. The cell morphology of the BBB model was observed using an inverted microscope. The function of BBB was measured with transendothelial electrical resistance (TEER) and sodium fluorescein, and the viability, apoptosis, and migration of pericytes were detected by cell counting kit-8, flow cytometry, and Transwell migration assay.

BMECs were positive staining for Factor-VIII, and pericytes were positive staining for the α-SMA and NG2. EA serum improved cell morphology of the BBB model, increased TEER and decreased sodium fluorescein in OGD/R condition. Besides, EA serum alleviated pericytes apoptosis rate and migration number, and enhanced pericytes viability rate in OGD/R condition.

EA serum protects against BBB damage induced by OGD/R in vitro, and this protection might be achieved by attenuating pericytes apoptosis and migration, as well as enhancing pericytes viability. The findings provided new evidence for EA as a medical therapy for ischemic stroke.

Silent Brain Infarction (SBI) has been found to be linked to an increased risk of cognitive impairment and future symptomatic stroke. Atrial fibrillation is a significant risk factor for SBI. Even in low-risk atrial fibrillation patients, the incidence of SBI remains high. This study aims to investigate the risk factors for SBI in Nonvalvular Atrial Fibrillation (NVAF) patients with a CHA2DS2-VASc score of 0 to 1.

A total of 301 consecutive low-risk NVAF patients (male: CHA2DS2-VASc=0, female: CHA2DS2-VASc=1) were enrolled. According to brain Magnetic Resonance Imaging (MRI), patients were divided into SBI (n=90) and non-SBI (n=211) groups. Baseline characteristics, blood parameters, and echocardiography results were analyzed. Multivariate logistic regression was performed to identify independent predictors. Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the diagnostic power of the relevant risk factors.

The study revealed that neutrophil count, monocyte count, Platelet-To-Lymphocyte Ratio (PLR), neutrophil-to-high density lipoprotein cholesterol ratio (NHR), and left atrial diameter (LAD) were significantly higher in the SBI group than non-SBI group (p <0.05). Multivariate logistic regression analysis identified PLR (OR, 1.004; 95%CI 1.001-1.007; p =0.026) and LAD (OR 1.092; 95%CI 1.054-1.130; p <0.001) as the independent risk factors associated with SBI. The ROC showed that the Area Under the Curve (AUC) of PLR is 0.589 (95%CI 0.515-0.662; p =0.015) with an optimal cut-off point of 151 (sensitivity 43.3%, specificity 74.6%). The AUC of LAD is 0.676 (95%CI 0.606-0.746; p <0.001) with an optimal cut-off point of 39 mm (sensitivity 61.1%, specificity 72.0%). The AUC of PLR combined with LAD is 0.711 (95%CI 0.646-0.777; p <0.001) with a sensitivity of 63.3% and specificity of 73.5% for SBI.

PLR and LAD can be independent risk factors for SBI in NVAF patients with low CHA2DS2-VASc scores. The combination of the two factors can enhance the predictive ability of SBI in these patients.

This study aimed to explore Malignant Brain Edema (MBE) and associated factors in patients with Large Hemispheric Infarction (LHI) following early reperfusion therapy.

We consecutively and retrospectively enrolled a cohort of 114 LHI patients who had received early reperfusion therapy, including Intravenous Thrombolysis (IVT) or Endovascular Therapy (EVT) at the hyperacute stage of stroke between January 2009 and December 2018. MBE was defined as a midline shift ≥5 mm, accompanied by signs of herniation. Multivariate logistic analyses were conducted to identify independent factors associated with MBE in LHI patients following early reperfusion therapy.

Among the enrolled patients, 69 (60.53%) were treated with IVT alone and 45 (39.47%) with EVT. Successful recanalization was achieved in 56 (49.12%) patients, while complete recanalization was achieved in 38 (33.33%) patients. After early reperfusion therapy, 50 (43.86%) developed MBE in LHI patients. The MBE group showed higher rates of in-hospital death (54% vs. 4.69%), 3-month mortality (64% vs. 10.94%), and 3-month unfavorable outcomes (90% vs. 64.06%) (all p<0.01). Neither different reperfusion therapy (EVT vs. IVT alone) nor different recanalization status (complete recanalization or not) was independently associated with the development of MBE in LHI patients following reperfusion therapy in multivariate analyses. MBE was independently associated with age [Odds Ratio (OR) 0.953, 95% confidence interval (CI) 0.910-0.999, p =0.044], right hemisphere stroke (OR 4.051, 95% CI 1.035-15.860, p =0.045), previous ischemic stroke or TIA (OR 0.090, 95% CI 0.014-0.571, p =0.011), and hypodensity >1/3 MCA territory (OR 8.071, 95% CI 1.878-34.693, p =0.005). Meanwhile, patients with lower baseline Alberta Stroke Program Early CT Score (ASPECTS) had a trend of higher incidence of MBE following reperfusion therapy (OR 0.710, 95% CI 0.483-1.043, p =0.081).

MBE occurred in nearly one-half of LHI patients following early reperfusion therapy and was related to poor outcomes. An increased risk of MBE was found to be associated with younger age, right hemisphere stroke, absence of a history of ischemic stroke or TIA, and hypodensity >1/3 MCA region on baseline CT images.