Current Neurovascular Research - Volume 20, Issue 3, 2023

Background: There has been a protracted effort to identify reliable targets for migraine. It is believed that each year, hundreds of millions of individuals worldwide suffer from migraines, making this widespread neurological ailment the second leading cause of years of disability worldwide. The rationale of this study is to identify the major targets involved in migraine attacks. Methods: For this review, specialized databases were searched, such as PubMed, EMBASE, DynaMed Plus, and Science Direct databases that included the pathophysiological mechanisms of migraine, focusing on in vitro and in vivo studies in the clinical management of migraine. Results: Calcitonin gene-related peptide, Pituitary adenylate cyclase-activating polypeptide (PACAP), NOD-like receptor Protein (NLRP3), Serotonin, and some other neuroinflammatory biomarkers are collectively responsible for the cerebral blood vessel dilation and involved in the nociceptive pain which leads to migraine attack. Conclusion: Migraine biomarkers such as CGRP, PACAP, NLRP3, Nitric oxide synthase, MMP9, and Serotonin could be targets for developing drugs. Present marketed medications temporarily reduce symptoms and pain and have serious cardiovascular side effects. It is suggested that herbal treatment may help prevent migraine attacks without adverse effects. Natural biomolecules that may give better treatment than the present marketed medication and full fledge research should be carried out with natural biomarkers by the Network Pharmacological approach.

Disorders of metabolism affect multiple systems throughout the body but may have the greatest impact on both central and peripheral nervous systems. Currently available treatments and behavior changes for disorders that include diabetes mellitus (DM) and nervous system diseases are limited and cannot reverse the disease burden. Greater access to healthcare and a longer lifespan have led to an increased prevalence of metabolic and neurodegenerative disorders. In light of these challenges, innovative studies into the underlying disease pathways offer new treatment perspectives for Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease. Metabolic disorders are intimately tied to neurodegenerative diseases and can lead to debilitating outcomes, such as multi-nervous system disease, susceptibility to viral pathogens, and long-term cognitive disability. Novel strategies that can robustly address metabolic disease and neurodegenerative disorders involve a careful consideration of cellular metabolism, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP-activated protein kinase (AMPK), growth factor signaling, and underlying risk factors such as the apolipoprotein E (APOE-ε4) gene. Yet, these complex pathways necessitate comprehensive understanding to achieve clinical outcomes that target disease susceptibility, onset, and progression.

Background: A protective and regulatory barrier between the blood and the brain is constituted by the blood-brain barrier (BBB), which comprises microvascular endothelial cells providing homeostatic regulation of the central nervous system (CNS). Inflammation compromises the BBB and contributes to many CNS disorders. Anti-inflammatory effects are exerted by glucocorticoids (GCs) on a variety of cells. These GCs include dexamethasone (Dex), which is used for the treatment of inflammatory diseases and recently for the treatment of COVID-19. Aim: The purpose of this study was to determine whether low or high concentrations of Dex can attenuate the inflammatory response induced by lipopolysaccharide (LPS) in the in vitro BBB model. Methods: Brain endothelial cells (bEnd.5) were cultured and exposed to LPS (100ng/ml) and subsequently co-treated with Dex to investigate whether selected concentrations of Dex (0.1, 5, 10, 20μM) can modulate the inflammatory effects of LPS on bEnd.5 cells. Cell viability, cell toxicity, and cell proliferation were investigated, as well as the monitoring of membrane permeability (Trans Endothelial Electrical Resistance-TEER), and Enzyme-Linked Immune Assay (ELISA) kits were used to identify and quantify the presence of inflammatory cytokines (TNF-α and IL-1β). Results: Dex, at a lower dosage (0.1μM, but not higher doses), was able to attenuate the inflammatory effects of LPS on bEnd.5 cells. Lower doses of Dex (0.1μM) had no detrimental effects on bEnd.5 cells, while higher Dex doses (5-20μM) decreased bEnd.5 viability, increased bEnd.5 cell toxicity, increased bEnd.5 cell monolayer permeability, and increased proinflammatory cytokine secretion. Conclusion: These results indicate that treatment of brain vascular inflammation with low doses of Dex should be advocated, while higher doses promote vascular inflammation.

Background: Electroacupuncture (EA) treatment has been recommended by World Health Organization (WHO) for years on cerebral ischemia treatment, but the specific mechanism is still elusive. Studies have shown that EA can relieve brain damage after ischemic stroke by inhibiting programmed cell death (PCD), such as apoptosis, necroptosis, and autophagy. Ferroptosis, a unique form of cell death, has been highlighted recently and found to occur in I/R injury. We, therefore, investigated whether EA plays an essential role in relieving cerebral I/R injury via ferroptosis. Methods: The modified MCAO/R rats model was established and then divided into four groups with or without EA treatment. Neurological deficit score and TTC staining were used to evaluate the neurological deficit and infarct volume of each group. Transmission electron microscope (TEM) and immunofluorescence staining were applied for mitochondrial ultrastructure and ROS accumulation observation, respectively. The proteins and mRNA expression of ACSL4, TFR1, and GPX4 were assessed by western blot and qPCR to detect the progress of ferroptosis. Results: EA treatment improved neurological deficits and reduced infarct volume. Moreover, EA significantly relieved the mitochondrial morphological changes and inhibited ROS Production in MCAO rats. In terms of its mechanism, EA obviously decreased the ACSL4 and TFR1 expressions and promoted GPX4 levels in MCAO/R model rats. Conclusion: These findings indicate that EA might play an essential role in relieving cerebral I/R injury via ferroptosis.

Background: Contrast extravasation (CE) on brain non-contrast computed tomography (NCCT) after endovascular therapy (EVT) is commonly present in patients with acute ischemic stroke (AIS). Substantial uncertainties remain about the relationship between the spatial location of CE and symptomatic intracranial hemorrhage (sICH). Therefore, this study aimed to evaluate this association. Methods: We performed a retrospective screening on consecutive patients with AIS due to LVO (AIS-LVO) who had CE on NCCT immediately after EVT for anterior circulation large vessel occlusion (LVO). We used the Alberta stroke program early CT Score (ASPECTS) scoring system to estimate the spatial location of CE. Multivariable logistic regression was performed to achieve the risk factors of sICH. Results: In this study, 115 of 153 (75.1%) anterior circulation AIS-LVO patients had CE on NCCT. After excluding 9 patients, 106 patients were enrolled in the final analysis. In multivariate regression analysis, atrial fibrillation (AF) (adjusted OR [aOR] 6.833, 95% confidence interval [CI] 1.331-35.081, P = 0.021) and CE-ASPECTS (aOR 0.602, 95% CI 0.411-0.882 P = 0.009) were associated with sICH. In subgroup analysis, CE at the internal capsule (IC) region was an independent risk factor for sICH (aOR 5.992, 95% CI 1.010-35.543 P < 0.05). These and conventional variables were incorporated as a predict model, with AUC of 0.899, demonstrating good discrimination and calibration for sICH in this study cohort. Conclusion: The spatial location of CE on NCCT immediately after EVT was an independent and strong risk factor for sICH in acute ischemic stroke patients.

Background: Physical activity in Amyotrophic Lateral Sclerosis (ALS) plays a controversial role. In some epidemiological studies, both recreational or professional sport exercise has been associated to an increased risk for ALS but the mechanisms underlying the effects of exercise have not been fully elucidated in either patients or animal models. Methods: To better reproduce the influence of this environmental factor in the pathogenesis of ALS, we exposed SOD1^G93A low-copy male mice to multiple exercise sessions at asymptomatic and pre-symptomatic disease stages in an automated home-cage running-wheel system for about 3 months. Results: Repeated voluntary running negatively influenced disease progression by anticipating disease onset, impairing neuromuscular transmission, worsening neuromuscular decline, and exacerbating muscle atrophy. Muscle fibers and neuromuscular junctions (NMJ) as well as key molecular players of the nerve-muscle circuit were similarly affected. Conclusion: It thus appears that excessive physical activity can be detrimental in predisposed individuals and these findings could model the increased risk of developing ALS in predisposed and specific professional athletes.

Background: To determine the association of cardiovascular risk factors with the presence and anatomic location of CMBs and construct a factor-based evaluating model to predict a high CMBs burden. Methods: We assessed the relation of age, male, various cardiovascular risk factors, medication use, stroke histories and white matter hyperintensities (WMH) to the presence and location of CMBs with univariate analysis and multiple logistic regression. Finally, we added risk factors for a high CMBs burden to a factor-based evaluating model score. Results: 485 patients were included in our study. CMBs were more prevalent with advanced age, male sex, more cardiovascular risk factors and WMH. Alcohol use, hemorrhagic stroke history and the degree of deep white matter hyperintensity (DWMH) were independent predictors for a high CMBs burden (≥10). We finally structured a prediction model-HPSAD3 that consisted of hypertension, alcohol use, hemorrhagic stroke history and WMH to predict a high CMBs burden. The model-HPSAD3 has a higher positive predict value (77.08%) and negative predict value (75.89%) to predict a high CMBs burden when the cut-off score is 4. Conclusions: Hypertension, alcohol use, hemorrhagic stroke history and WMH were added into the model- HPSAD3, and there was a higher possibility of patients with CMBs ≥10 when the score of HPSAD3 ≥4.

Background: The association between baseline red blood cell distribution width (RDW) and hemoglobin levels and outcomes after acute intracerebral hemorrhage (ICH) is not well studied. We aimed to investigate the association between baseline RDW and hemoglobin levels with early hematoma expansion (HE) and mortality at 3 months and 1 year in acute ICH patients. Methods: A total of 393 ICH patients from January 2014 to February 2019 were included. Patients were divided into four groups based on quartiles of RDW and hemoglobin levels at admission, respectively. Logistic regression models were used to estimate the effect of the levels of RDW and hemoglobin on early HE (absolute hematoma growth >6 mL from baseline to follow-up) and allcaused mortality at 3 months and 1 year. Results: There were no significant associations between baseline RDW and hemoglobin levels and early HE. The 3-month mortality (adjusted odds ratio [OR] 2.88; 95% confidence intervals [CI] 0.96-8.64) and 1-year mortality (adjusted OR 3.16, 95% CI 1.08-9.21) was significantly higher in patients with the highest RDW level (Q4) compared to those with the lowest RDW level (Q1). Moreover, patients with the lowest hemoglobin level were significantly associated with increased odds of all-cause mortality at 3-month (adjusted OR 3.95, 95% CI 1.26-12.4) and 1-year (adjusted OR 4.42, 95% CI 1.56-12.5) compared to those with highest hemoglobin level. Conclusion: In patients with acute ICH, a higher level of RDW at admission significantly increased the risk of all-cause mortality at 1 year. Moreover, a decreased hemoglobin level at admission was also associated with a higher risk of all-cause mortality at 3 months and 1 year.

Background: Lacunae and white matter hyperintensity (WMH) are two crucial imaging biomarkers of cerebral small vessel disease (CSVD). Multiple studies have revealed a close relationship between WMH and lacunae and found that a double penumbra existed at the edge of WMH that affects lacunae formation. The study aimed to explore the spatial distribution characteristics and possible influencing factors of lacuna in relation to white matter hyperintensity in patients with CSVD. Methods: A total of 480 CSVD patients with WMH and with or without lacunae were included. Data about blood biochemical indicators, cerebrovascular CT angiography, 24-hour ambulatory blood pressure and ambulatory electrocardiogram, brain magnetic resonance imaging, and transcranial Doppler ultrasound were gathered from all subjects. They were categorised into four groups based on the spatial interaction between lacunae and WMH. Univariate analyses and multiple logistic regression analyses were used to compare the differences in traditional vascular risk factors, heart rate and blood pressure indicators, arterial pulsatility index (PI) values, and arterial stenosis among different groups. Results: The average age of 480 patients was (58.63 ± 11.91) years, with 347 males (72.3%). Univariate analysis indicated that age, fasting blood glucose, triglycerides, total cholesterol, highdensity lipoprotein, 24-hour and daytime and night systolic and diastolic blood pressure, nocturnal heart rate, heart rate variability, PI values of ipsilateral and contralateral MCA (middle cerebral artery) and ICA (Internal carotid artery) of the lacunae, Fazekas score of PWMH (periventricular white matter hyperintensities), the proportion of MCA or ICA with stenosis rate over 50% on the ipsilateral side of the lacunae were significantly different between different groups (p < 0.05). High fasting blood glucose (OR=1.632, 95% CI= (1.128, 2.361), p =0.009), (OR=1.789, 95%CI= (1.270, 2.520), p = 0.001), (OR=1.806, 95% CI= (1.292, 2.524), p =0.001) was identified as a risk factor for lacunae formation by logistic regression analysis. Conclusion: High fasting blood glucose can be considered a risk factor for lacunae formation in patients with WMH. The more severe the PWMH and the higher the nocturnal heart rate, the more likely the lacunae, as well as PWMH, overlap completely. Ipsilateral arteriosclerosis and stenosis are independent risk factors for no contact between lacunae and PWMH.

Background: Genome-wide association studies (GWAS) have been used to explore the connections between genotypes and phenotypes by comparing the genotype frequencies of genetic changes in individuals with similar origins but distinct traits. Objectives: The aim is to employ the GWAS catalog to identify and investigate the various correlations between genotypes and phenotypes of the REST gene. Methods: In this study, we utilized a large dataset of GWAS comprising 62,218,976 individuals in 112 studies and 122 associations with 122 traits (www.ebi.ac.uk/gwas/genes/REST) from European, Asian, Hispanic, African ancestry up to 28 February 2023. Protein-association network evaluation and gene ontology enrichment study was utilized to evaluate the biological function of the discovered gene modules. Results: We identified several associations for both neurodevelopmental and neurodegenerative disorders linked to REST, as well as its mapped gene modules and their functional relationship networks. Conclusion: This work offers fresh insights into identifying risk loci of neurological disorders caused by REST.

Background: Through an analysis of the risk factors associated with patent foramen ovale (PFO)-related stroke (PS), we aimed to modify the Risk of Paradoxical Embolism (RoPE) to assess the risk of PS. Methods: A retrospective collection of ischemic stroke (IS) patients with PFO admitted to the Department of Neurology at Beijing Chaoyang Hospital was conducted. The patients were classified into PS and non-PS groups. PS risk factors and RoPE scoring were analyzed based on clinical data, laboratory indicators, and imaging data. Independent risk factors were incorporated into the RoPE scoring system for enhancement. Results: Significant differences were observed between the two groups regarding total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and uric acid levels. The transverse diameter of the left atrium was significantly larger in the non-PS group compared to the PS group. Multivariate logistic regression revealed that higher LDL-C levels and a smaller transverse diameter of the left atrium increased the risk of PS. The modified RoPE score was derived by assigning 1 point each for high LDL-C levels and the absence of transverse diameter enlargement in the left atrium. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves for the classical and modified RoPE score distinguishing PS were 0.661 and 0.798, respectively. Conclusion: LDL-C levels and transverse diameter of the left atrium were identified as independent risk factors for PS. The modified RoPE scoring system exhibited superior performance in assessing the risk of PS compared to the original RoPE score.