Dihydroergotamine protects against ischemic stroke by modulating microglial/macrophage polarization and inhibiting inflammation in mice.

OBJECTIVES: The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. RESULTS: From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1ß in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. CONCLUSION: This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

Erythropoietin-derived peptide ARA290 mediates brain tissue protection through the ß-common receptor in mice with cerebral ischemic stroke.

AIM: To explore the neuroprotective effects of ARA290 and the role of ß-common receptor (ßCR) in a mouse model of middle cerebral artery occlusion (MCAO). METHODS: This study included male C57BL/6J mice that underwent MCAO and reperfusion. The neuroprotective effect of ARA290 on MCAO-induced brain injury was investigated using neurological function tests (Longa and modified neurological severity score). Cerebral infarction was examined by 2, 3, 5-triphenyl tetrazolium chloride staining, neuronal apoptosis was assessed by immunofluorescence staining, blood parameters were measured using a flow cytometry-based automated hematology analyzer, liquid chromatography with tandem mass spectrometry was used to identify the serum metabolomics signature, inflammatory cytokines and liver index were detected by commercially available kits, and the protein levels of the erythropoietin (EPO) receptor and ßCR were measured by western blot. RESULTS: ARA290 exerted a qualitatively similar neuroprotective effect after MCAO as EPO. ARA290 significantly reduced neuronal apoptosis and the level of inflammatory cytokines in the brain tissue. However, ARA290's neuroprotective effect was significantly suppressed following the injection of siRNA against ßCR. CONCLUSION: ARA290 provided a neuroprotective effect via ßCR in cerebral ischemic mice without causing erythropoiesis. This study provides novel insights into the role of ARA290 in ischemic stroke intervention.

Annexin A6 mitigates neurological deficit in ischemia/reperfusion injury by promoting synaptic plasticity.

AIMS: Alleviating neurological dysfunction caused by acute ischemic stroke (AIS) remains intractable. Given Annexin A6 (ANXA6)'s potential in promoting axon branching and repairing cell membranes, the study aimed to explore ANXA6's potential in alleviating AIS-induced neurological dysfunction. METHODS: A mouse middle cerebral artery occlusion model was established. Brain and plasma ANXA6 levels were detected at different timepoints post ischemia/reperfusion (I/R). We overexpressed and down-regulated brain ANXA6 and evaluated infarction volume, neurological function, and synaptic plasticity-related proteins post I/R. Plasma ANXA6 levels were measured in patients with AIS and healthy controls, investigating ANXA6 expression's clinical significance. RESULTS: Brain ANXA6 levels initially decreased, gradually returning to normal post I/R; plasma ANXA6 levels showed an opposite trend. ANXA6 overexpression significantly decreased the modified neurological severity score (p = 0.0109) 1 day post I/R and the infarction area at 1 day (p = 0.0008) and 7 day (p = 0.0013) post I/R, and vice versa. ANXA6 positively influenced synaptic plasticity, upregulating synaptophysin (p = 0.006), myelin basic protein (p = 0.010), neuroligin (p = 0.078), and tropomyosin-related kinase B (p = 0.150). Plasma ANXA6 levels were higher in patients with AIS (1.969 [1.228-3.086]) compared to healthy controls (1.249 [0.757-2.226]) (p < 0.001), that served as an independent risk factor for poor AIS outcomes (2.120 [1.563-3.023], p < 0.001). CONCLUSIONS: This study is the first to suggest that ANXA6 enhances synaptic plasticity and protects against transient cerebral ischemia.

Prognostic Significance of Plasma VEGFA and VEGFR2 in Acute Ischemic Stroke-a Prospective Cohort Study.

Enhancement of vascular remodeling in affected brain tissue is a novel therapy for acute ischemic stroke (AIS). However, conclusions regarding angiogenesis after AIS remain ambiguous. Vascular endothelial growth factor A (VEGFA) and VEGF receptor 2 (VEGFR2) are potent regulators of angiogenesis and vascular permeability. We aimed to investigate the association between VEGFA/VEGFR2 expression in the acute stage of stroke and prognosis of patients with AIS. We enrolled 120 patients with AIS within 24 h of stroke onset and 26 healthy controls. Plasma levels of VEGFA and VEGFR2 were measured by enzyme-linked immunosorbent assay (ELISA). The primary endpoint was an unfavorable outcome defined as a modified Rankin Scale (mRS) score > 2 at 3 months after AIS. Univariate and multivariate logistic regression analyses were used to identify risk factors affecting prognosis. Plasma VEGFA and VEGFR2 were significantly higher in patients with AIS than in health controls, and also significantly higher in patients with unfavorable than those with favorable outcomes. Moreover, both VEGFA and VEGFR2 showed a significantly positive correlation with mRS at 3 months. Univariate and multivariate analyses showed VEGFA and VEGFR2 remained associated with unfavorable outcomes, and adding VEGFA and VEGFR2 to the clinical model significantly improved risk reclassification (continuous net reclassification improvement, 105.71%; integrated discrimination improvement, 23.45%). The new risk model curve exhibited a good fit with an area under the receiver operating characteristic curve (ROC) curve of 0.9166 (0.8658-0.9674). Plasma VEGFA and VEGFR2 are potential markers for predicting prognosis; thus these two plasma biomarkers may improve risk stratification in patients with AIS.

CCA repair or ECA ligation-Which middle cerebral artery occlusion is better in the reperfusion mouse model?

A reliable animal model is essential for ischemic stroke research. The implications of the external carotid artery (ECA) transection or common carotid artery (CCA) ligation have been described. Thus, a modified animal model, the CCA-repair model, has been established, and studies have shown that the CCA-repair model has potential advantages over the CCA-ligation model. However, whether the CCA-repair model is superior to the ECA-ligation model remains unclear. Sixty male C57BL/6 mice were randomly assigned to establish the CCA-repair (n = 34) or ECA-ligation (n = 26) models. Cerebral blood flow before middle cerebral artery occlusion (MCAO), immediately after MCAO and reperfusion were monitored and the operation duration, postoperative body weight, and food intake within 7 days, and the number of intraoperative and postoperative deaths within 7 days were recorded in the two models. Modified neurological severity scores and Bederson (0-5) scores were used to evaluate postoperative neurological function deficits on Days 1/3/5/7. 2,3,5-Triphenyltetrazolium chloride staining was used to quantify lesion volume on Day 7 after the operation. We found the establishment of the CCA-repair model required a longer total operation duration (p = 0.0175), especially the operation duration of reperfusion (p < 0.0001). However, there was no significant difference in body weight and food intake development, lesion volume and intragroup variability, neurological function deficits, mortality, and survival probability between the two groups. The CCA-repair model has no significant advantage over the ECA-ligation model. The ECA-ligation model is still a better choice for focal cerebral ischemia.

LC-MS/MS metabolomic profiling of the protective butylphthalide effect in cerebral ischemia/reperfusion mice.

OBJECTIVES: This study was designed to investigate metabolic biomarker changes and related metabolic pathways of Butylphthalide (NBP) on cerebral ischemia/reperfusion. METHODS: In this study, a mouse cerebral ischemia/reperfusion (I/R) model was prepared using the middle cerebral artery occlusion method, and neurobehavioral score and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining experiments were used to confirm the obvious NBP anti-cerebral ischemia effect. The protective effect of NBP in the mouse cerebral I/R model and its metabolic pathway and mechanism were investigated using mouse blood samples. RESULTS: The metabolic profiles of mice in the I/R+NBP, I/R, and sham groups were significantly different. Under the condition that I/R vs. sham was downregulated and I/R + NBP vs. I/R was upregulated, 88 differential metabolites, including estradiol, ubiquinone-2, 2-oxoarginine, and L-histidine trimethylbetaine, were screened and identified. The related metabolic pathways involved arginine and proline metabolism, oxidative phosphorylation, ubiquitin and other terpenoid-quinone biosynthesis, and estrogen signaling. CONCLUSIONS: Metabolomics was used to elucidate the NBP mechanism in cerebral ischemia treatment in mice, revealing synergistic NBP pharmacological characteristics with multiple targets.

Untargeted metabolomics uncovering neuroprotective effect of Dl-3-n-butylphthalide on improving cognitive impairment induced by chronic cerebral hypoperfusion in rats.

Chronic cerebral hypoperfusion (CCH) can cause cognitive impairments. Dl-3-n-butylphthalide (NBP) is widely used in neurological disorders; but, the role of NBP in CCH remains unclear. This study aimed to investigate the potential mechanism of NBP on CCH through untargeted metabolomics. Animals were divided into CCH, Sham, and NBP groups. A rat model of bilateral carotid artery ligation was used to simulate CCH. Cognitive function of the rats was assessed using the Morris water maze test. Additionally, we used LC-MS/MS to detect ionic intensities of metabolites between the three groups for off-target metabolism analysis and to screen for differential metabolites. The analysis showed an improvement in cognitive function in rats after NBP treatment. Moreover, metabolomic studies showed that the serum metabolic profiles of the Sham and CCH groups were significantly altered, and 33 metabolites were identified as potential biomarkers associated with the effects of NBP. These metabolites were enriched in 24 metabolic pathways.And the pathway of differential metabolite enrichment was further verified by immunofluorescence. Thus, the study provides a theoretical basis for the pathogenesis of CCH and the treatment of CCH by NBP, and supports a wider application of NBP drugs.

Autophagic degradation of LOX-1 is involved in the maintenance of vascular integrity injured by oxLDL and protected by Berberine.

Damage to vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) caused by oxidized low-density lipoprotein (oxLDL) contributes to cardiovascular and cerebrovascular diseases. Protection effects of Berberine (BBR) on the cardiovascular system have been reported, however, the molecular mechanism of vascular protection is still unclear. In this study, we established two hyperlipidemia models in zebrafish and VEC-VSMC co-culture using high-cholesterol food (HCF) and oxLDL, respectively. We demonstrated that HCF doubled total cholesterol and total glyceride levels, and BBR decreased these indices in a concentration-dependent manner. Lipid staining and hematoxylin-eosin staining revealed that BBR inhibited oxLDL-induced VSMC bulge-like proliferation and migration toward VECs and prevented the HCF-induced trunk vascular obstruction in zebrafish. Immunoblot analysis, cell immunofluorescence, co-immunoprecipitation assays, and transmission electron microscopy showed that oxLDL/HCF increased lectin-like oxLDL receptor-1 (LOX-1) expression at least 5-fold and significantly inhibited autophagolysosome formation in the blood vessel cells and in zebrafish. These observations were associated with endothelial-to-mesenchymal transition (EMT) in VECs and triggered VE-cadherin ectopic expression in VSMCs, and they were responsible for aberrant VSMC migration and vascular occlusion. However, BBR, by promoting autolysosome formation and degradation of LOX-1, reversed the above events and maintained intracellular homeostasis of vessel cells and vascular integrity. In conclusion, regulation of autophagy may be an effective approach to treating oxLDL-induced cardiovascular diseases by reducing LOX-1 protein level. BBR can protect blood vessels by adjusting the oxLDL-LOX-1-EMT-autophagy axis. This study is a step toward the development of new applications of BBR.

Is the ß Common Receptor the Key Molecule for the Protective Effect of Erythropoietin?

Erythropoietin is generally assumed to have protective effects against multiple diseases, especially ischemic stroke, and myocardial infarctions. The theory behind Erythropoietin's (EPO) protective effects has been misconstrued in the scientific community to a degree, with assumptions made that the ß common receptor (ßcR) in the heteroreceptor EPO receptor (EPOR)/ßcR is responsible for these protective effects. Our purpose with this opinion article is to convey our concern for the general assumption of the importance of ßcR in EPO's protective effect and to emphasize the necessity of further research in this field.

Association of admission neutrophil serine proteinases levels with the outcomes of acute ischemic stroke: a prospective cohort study.

BACKGROUND: Neutrophil serine proteinases (NSPs), released by activated neutrophils, are key proteins involved in the pathophysiologic processes of stroke. NSPs are also implicated in the process and response of thrombolysis. This study aimed to analyze three NSPs (neutrophil elastase, cathepsin G, and proteinase 3) in relation to acute ischemic stroke (AIS) outcomes and in relation to the outcomes of patients treated with intravenous recombinant tissue plasminogen activator (IV-rtPA). METHODS: Among 736 patients prospectively recruited at the stroke center from 2018 to 2019, 342 patients diagnosed with confirmed AIS were included. Plasma neutrophil elastase (NE), cathepsin G (CTSG), and proteinase 3 (PR3) concentrations were measured on admission. The primary endpoint was unfavorable outcome defined as modified Rankin Scale score 3-6 at 3 months, and the secondary endpoints were symptomatic intracerebral hemorrhage (sICH) within 48 h, and mortality within 3 months. In the subgroup of patients who received IV-rtPA, post-thrombolysis early neurological improvement (ENI) (defined as National Institutes of Health Stroke Scale score = 0 or decrease of ≥ 4 within 24 h after thrombolysis) was also included as the secondary endpoint. Univariate and multivariate logistic regression analyses were performed to evaluate the association between NSPs levels and AIS outcomes. RESULTS: Higher NE and PR3 plasma levels were associated with the 3-month mortality and 3-month unfavorable outcome. Higher NE plasma levels were also associated with the risk of sICH after AIS. After adjusting for potential confounders, plasma NE level > 229.56 ng/mL (odds ratio [OR] = 4.478 [2.344-8.554]) and PR3 > 388.77 ng/mL (OR = 2.805 [1.504-5.231]) independently predicted the 3-month unfavorable outcome. Regarding rtPA treatment, patients with NE plasma concentration > 177.22 ng/mL (OR = 8.931 [2.330-34.238]) or PR3 > 388.77 ng/mL (OR = 4.275 [1.045-17.491]) were over 4 times more likely to suffer unfavorable outcomes after rtPA treatment. The addition of NE and PR3 to clinical predictors of unfavorable functional outcome after AIS and the outcome after rtPA treatment improved discrimination as well as reclassification (integrated discrimination improvement = 8.2% and 18.1%, continuous net reclassification improvement = 100.0% and 91.8%, respectively). CONCLUSIONS: Plasma NE and PR3 are novel and independent predictors of 3-month functional outcomes after AIS. Plasma NE and PR3 also possess predictive value to identify patients with unfavorable outcomes after rtPA treatment. NE is probably an important mediator of the effects of neutrophils on stroke outcomes, which worth further investigation.

Inhibition of the JAK2/STAT3 pathway and cell cycle re-entry contribute to the protective effect of remote ischemic pre-conditioning of rat hindlimbs on cerebral ischemia/reperfusion injury.

AIMS: Remote ischemic pre-conditioning (RIPC) protects against ischemia/reperfusion (I/R) injury. However, the mechanisms underlying this protection remain unclear. In the present study, we investigated the role of Janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway and cell cycle arrest, and their relationship with neuronal apoptosis following RIPC. METHODS: A rat cerebral I/R injury model was induced by middle cerebral artery occlusion (MCAO), and AG490 was used to investigate the mechanisms of RIPC. p-JAK2-, p-STAT3-, cyclin D1-, and cyclin-dependent kinase 6 (CDK6) expression was assessed by Western blotting and immunofluorescence staining. RESULTS: RIPC reduced the infarct volume, improved neurological function, and increased neuronal survival. Furthermore, p-JAK2 and p-STAT3 were detected during the initial phase of reperfusion; the expression levels were significantly increased at 3 and 24 h after reperfusion and were suppressed by RIPC. Additionally, the MCAO-induced upregulation of the cell cycle regulators cyclin D1 and CDK6 was ameliorated by RIPC. Meanwhile, cyclin D1 and CDK6 were colocalized with p-STAT3 in the ischemic brain. CONCLUSION: RIPC ameliorates the induction of the JAK2/STAT3 pathway and cell cycle regulators cyclin D1 and CDK6 by MCAO, and this net inhibition of cell cycle re-entry by RIPC is associated with downregulation of STAT3 phosphorylation.

MicroRNA-193a-5p Rescues Ischemic Cerebral Injury by Restoring N2-Like Neutrophil Subsets.

Circulating neutrophils are activated shortly after stroke and in turn affect the fate of ischemic brain tissue, and microRNAs (miRNA) participate in regulating neuroinflammation. We probed the role of neutrophilic miRNA in ischemic stroke. miR-193a-5p was decreased in circulating neutrophils of acute ischemic stroke (AIS) patients and healthy controls. In another set of AIS patients treated with recombinant tissue plasminogen activator, higher neutrophilic miR-193a-5p levels were associated with favorable outcomes at 3 months and non-symptomatic intracerebral hemorrhage. An experimental stroke model and human neutrophil-like HL-60 cells were further transfected with agomiR-193a-5p/antagomiR-193a-5p or ubiquitin-conjugating enzyme V2 (UBE2V2)-siRNA prior to model induction for in vivo and in vitro studies. Results of 2,3,5-triphenyl tetrazolium chloride staining and neurological function evaluations at post-experimental stroke showed that intravenous agomiR-193a-5p transfusion protected against ischemic cerebral injury in the acute stage and promoted neurological recovery in the subacute stage. This protective role was suggested to correlate with neutrophil N2 transformation based on the N2-like neutrophil proportions in the bone marrow, peripheral blood, and spleen of the experimental stroke model and the measurement of neutrophil phenotype-associated molecule levels. Mechanistically, analyses indicated that UBE2V2 might be a target of miR-193a-5p. Cerebral injury and neuroinflammation aggravated by miR-193a-5p inhibition were reversed by UBE2V2 silencing. In conclusion, miR-193a-5p protects against cerebral ischemic injury by restoring neutrophil N2 phenotype-associated neuroinflammation suppression, likely, in part, via UBE2V2 induction.

Explore the role of long noncoding RNAs and mRNAs in intracranial atherosclerotic stenosis: From the perspective of neutrophils.

CONTEXT: Circulating neutrophils and long noncoding RNAs (lncRNAs) play various roles in intracranial atherosclerotic stenosis (ICAS). OBJECTIVE: Our study aimed to detect differentially expressed (DE) lncRNAs and mRNAs in circulating neutrophils and explore the pathogenesis of atherosclerosis from the perspective of neutrophils. METHODS: Nineteen patients with ICAS and 15 healthy controls were enrolled. The peripheral blood of the participants was collected, and neutrophils were separated. The expression profiles of lncRNAs and mRNAs in neutrophils from five patients and five healthy controls were obtained, and DE lncRNAs and mRNAs were selected. Six lncRNAs were selected and validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and ceRNA and lncRNA-RNA binding protein (RBP)-mRNA networks were constructed. Correlation analysis between lncRNAs and mRNAs was performed. Functional enrichment annotations were also performed. RESULTS: Volcano plots and heat maps displayed the expression profiles and DE lncRNAs and mRNAs, respectively. The qRT-PCR results revealed that the four lncRNAs showed a tendency consistent with the expression profile, with statistical significance. The ceRNA network revealed three pairs of regulatory networks: lncRNA RP3-406A7.3-NAGLU, lncRNA HOTAIRM1-MVK/IL-25/GBF1/CNOT4/ANKK1/PLEKHG6, and lncRNA RP11-701H16.4-ZNF416. The lncRNA-RBP-mRNA network showed five pairs of regulatory networks: lncRNA RP11-701H16.4-TEK, lncRNA RP11-701H16.4-MED17, lncRNA SNHG19-NADH-ubiquinone oxidoreductase core subunit V1, lncRNA RP3-406A7.3-Angel1, and lncRNA HOTAIRM1-CARD16. CONCLUSIONS: Our study identified and verified four lncRNAs in neutrophils derived from peripheral blood, which may explain the transcriptional alteration of neutrophils during the pathophysiological process of ICAS. Our results provide insights for research related to the pathogenic mechanisms and drug design of ICAS.

Neutrophilic noncoding RNAs predict outcomes of acute ischemic stroke patients treated with recombinant tissue plasminogen activator.

There's no evidence demonstrating the association between noncoding RNAs levels before IV recombinant tissue plasminogen activator (rtPA) administration and the outcomes of acute ischemic stroke (AIS). 145 AIS patients received rtPA treatment were recruited at the stroke center from 2018 to 2019, and 103 patients were included in this study. A panel of noncoding RNAs (miRNA-23a, miRNA-193a, miRNA-128, miRNA-99a, miRNA-let-7a, miRNA-494, miRNA-424, and lncRNA H19) were measured in the circulating neutrophils of AIS patients before rtPA treatment. Endpoints included excellent outcome (modified Rankin Scale score [mRS] 0-1) or poor outcome (mRS > 1) at 3 months and symptomatic intracerebral hemorrhage (sICH) after rtPA treatment. Among the eight noncoding RNAs detected in circulating neutrophils of the 103 participants, miRNA-23a levels were associated with the stroke severity on admission and symptom progression at 24 h after rtPA treatment. A noncoding RNA score composed of miRNA-23a, miRNA-99a, and lncRNA H19 was screened to predict the functional outcome at 3 months and the incidence of sICH after rtPA treatment. In the logistic regression analysis, the noncoding RNA score ≥ -0.336 (OR = 2.862 [1.029-7.958], p = 0.044) was an independent predictor of the poor outcome at 3 months after adjustment of clinical variables, the addition of the noncoding RNA score to the clinical model improved the discrimination (IDI% = 4.68 [0.65-8.71], p = 0.020), as well as the net reclassification (NRI% = 33.04 [0.54-71.49], p = 0.016). The noncoding RNA score ≥ -0.336 (OR = 5.250 [1.096-25.135], p = 0.038) was also independently predicted the sICH, the addition of the noncoding RNA score to the clinical variables improved discrimination and reclassification as well. The noncoding RNA score was also associated with the infarct volume and symptom improvement at 7 days after rtPA treatment. In conclusion, a higher neutrophilic noncoding RNA score provides predictive value to identify AIS patients with worse outcomes after rtPA treatment. miRNA-23a, miRNA-99a, and lncRNA H19 are worth further investigation for their effects in thrombolysis after AIS.

Lomitapide ameliorates middle cerebral artery occlusion-induced cerebral ischemia/reperfusion injury by promoting neuronal autophagy and inhibiting microglial migration.

AIMS: Stroke has a high incidence and is a disabling condition that can lead to severe cognitive, motor, and sensory dysfunction. In this study, we employed a drug repurposing strategy to investigate the neuroprotective effect of lomitapide on focal ischemic brain injury and explore its potential mechanism of action. METHODS: Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male C57BL/6 mice and simulated by oxygen-glucose deprivation in N2a-BV2 cells in co-cultivation. RESULTS: Lomitapide significantly increased the survival rate, reduced the neuronal tissue loss, and improved the neurological function after MCAO. Furthermore, lomitapide could increase the expression of LC3-II, reduce the expression of P62 and LAMP2, promote autophagic flux, and inhibit apoptosis by increasing and inhibiting the expression of the apoptosis-associated proteins Bcl-2 and Bax, respectively. In addition, lomitapide inhibited the migration of pro-inflammatory microglia. CONCLUSION: Lomitapide is a lipid-lowering drug, and this is the first study to explore its protective effect on ischemic nerve injury in vitro and in vivo. Our results suggest that lomitapide can be repositioned as a potential therapeutic drug for the treatment of stroke.

Nrf2 Pathway and Autophagy Crosstalk: New Insights into Therapeutic Strategies for Ischemic Cerebral Vascular Diseases.

Cerebrovascular disease is highly prevalent and has a complex etiology and variable pathophysiological activities. It thus poses a serious threat to human life and health. Currently, pathophysiological research on cerebrovascular diseases is gradually improving, and oxidative stress and autophagy have been identified as important pathophysiological activities that are gradually attracting increasing attention. Many studies have found some effects of oxidative stress and autophagy on cerebrovascular diseases, and studies on the crosstalk between the two in cerebrovascular diseases have made modest progress. However, further, more detailed studies are needed to determine the specific mechanisms. This review discusses nuclear factor erythroid 2-related factor 2 (Nrf2) molecules, which are closely associated with oxidative stress and autophagy, and the crosstalk between them, with the aim of providing clues for studying the two important pathophysiological changes and their crosstalk in cerebrovascular diseases as well as exploring new target treatments.

Elevated plasma syndecan-1 as glycocalyx injury marker predicts unfavorable outcomes after rt-PA intravenous thrombolysis in acute ischemic stroke.

Purpose: We aimed to examine the prognostic value of syndecan-1 as a marker of glycocalyx injury in patients with acute ischemic stroke (AIS) receiving rt-PA intravenous thrombolysis. Methods: The study included 108 patients with AIS treated with rt-PA intravenous thrombolysis and 47 healthy controls. Patients were divided into unfavorable and favorable prognosis groups based on modified Rankin Scale scores. Univariate and multivariate logistic regression analyses were used to determine risk factors affecting prognosis. Risk prediction models presented as nomograms. The predictive accuracy and clinical value of the new model were also evaluated. Results: Plasma levels of syndecan-1 were significantly higher in patients with AIS than in controls (p < 0.05). Univariate analysis indicated that higher levels of syndecan-1 were more frequent in patients with poor prognosis than in those with good prognosis (t = -4.273, p < 0.001). Syndecan-1 alone and in combination with other factors predicted patient outcomes. After adjusting for confounding factors, syndecan-1 levels remained associated with poor prognosis [odds ratio, 1.024; 95% confidence interval (CI), 1.010-1.038]. The risk model exhibited a good fit, with an area under the receiver operating characteristic curve of 0.935 (95% CI, 0.888-0.981). The categorical net reclassification index (NRI) and continuous NRI values were >0. The integrated discrimination improvement value was 0.111 (95% CI, 0.049-0.174, p < 0.001). Decision curve analysis indicated that the model incorporating syndecan-1 levels was more clinically valuable than the conventional model. Conclusion: Plasma syndecan-1 levels represent a potential marker of prognosis of AIS following intravenous thrombolysis. Adding syndecan-1 to the conventional model may improve risk stratification.

Berberine protects against chronic cerebral hypoperfusion-induced cognitive impairment and hippocampal damage via regulation of the ERK/Nrf2 pathway.

Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) seriously affects the quality of life of elderly patients and places a great burden on society and family. With the development of traditional Chinese medicine (TCM), TCM approaches to the prevention and treatment of senile ischemic cerebrovascular disease has received increasing attention. In this study, rats with bilateral common carotid artery occlusion (BCCAO) were treated with berberine (BBR). Their learning and memory function, neuronal injury and repair, the extracellular regulatory protein kinase (ERK)/nuclear factor-E2-related factor 2 (Nrf2) signaling pathway, and impairment and improvement of the blood-brain barrier (BBB) were evaluated. This study found that BBR can alleviate the pathological injury to the brain, reduce neuronal loss and promote neuronal cell survival after CCH by interfering with the ERK/Nrf2 signaling pathway. BBR can reduce BBB injury in CCH rats by inhibiting the expression of VEGF-A and MMP-9 in plasma, which reveals a protective effect of BBR on vascular cognitive impairment. This study provides a new research direction for BBR in the treatment of ischemic cerebrovascular disease.

VEGF, a Key Factor for Blood Brain Barrier Injury After Cerebral Ischemic Stroke.

Blood brain barrier (BBB) injury is an important factor affecting the prognosis of ischemic stroke. Extensive research on BBB injury has revealed that blood vessels and neural networks are interdependent and interrelated during and after the development of the brain. An array of signaling molecules, known as angioneurins, can affect both blood vessels and neural networks simultaneously. Angioneurins not only regulate the angiogenesis and remodeling process of the vascular system, but also act as neurotrophic and neuroprotective factors, or serve as guide molecules for axons. Vascular endothelial growth factor (VEGF) is a type of angioneurin that is expressed in neurons, astrocytes, macrophages, and vascular endothelial cells in ischemic and hypoxic brain tissues after cerebral ischemia. VEGF can increase and induce the destruction of the endothelial barrier in the early stages of cerebral ischemia. Both the upregulation of endogenous VEGF levels and the use of exogenous VEGF are harmful in the acute stage of stroke. However, the harmful effects of VEGF on vascular integrity are transient. Several studies have shown that VEGF regulates angiogenesis, neurogenesis, neurite growth and brain edema after cerebral ischemia. Therefore, it is crucial to understand the dual role of VEGF in ischemic stroke. The following will focus on the damage caused by VEGF to the BBB in the context of cerebral ischemic stroke, as well as therapeutic studies targeting VEGF.