Cerebral Ischemia Research Articles

A mechanistic systems biology model of brain microvascular endothelial cell signaling reveals dynamic pathway-based therapeutic targets for brain ischemia

Ischemic stroke is a significant threat to human health. Currently, there is a lack of effective treatments for stroke, and progress in new neuron-centered drug target development is relatively slow. On the other hand, studies have demonstrated that brain microvascular endothelial cells (BMECs) are crucial components of the neurovascular unit and play pivotal roles in ischemic stroke progression. To better understand the complex multifaceted roles of BMECs in the regulation of ischemic stroke pathophysiology and facilitate BMEC-based drug target discovery, we utilized a transcriptomics-informed systems biology modeling approach and constructed a mechanism-based computational multipathway model to systematically investigate BMEC function and its modulatory potential. Extensive multilevel data regarding complex BMEC pathway signal transduction and biomarker expression under various pathophysiological conditions were used for quantitative model calibration and validation, and we generated dynamic BMEC phenotype maps in response to various stroke-related stimuli to identify potential determinants of BMEC fate under stress conditions. Through high-throughput model sensitivity analyses and virtual target perturbations in model-based single cells, our model predicted that targeting succinate could effectively reverse the detrimental cell phenotype of BMECs under oxygen and glucose deprivation/reoxygenation, a condition that mimics stroke pathogenesis, and we experimentally validated the utility of this new target in terms of regulating inflammatory factor production, free radical generation and tight junction protection in vitro and in vivo. Our work is the first that complementarily couples transcriptomic analysis with mechanistic systems-level pathway modeling in the study of BMEC function and endothelium-based therapeutic targets in ischemic stroke.

Mechanisms of fibrinogen trans-activation of the EGFR/Ca2+ signaling axis to regulate mitochondrial transport and energy transfer and inhibit axonal regeneration following cerebral ischemia.

Ischemic stroke results in inhibition of axonal regeneration but the roles of fibrinogen (Fg) in neuronal signaling and energy crises in experimental stroke are under-investigated. We explored the mechanism of Fg modulation of axonal regeneration and neuronal energy crisis after cerebral ischemia using a permanent middle cerebral artery occlusion (MCAO) rat model and primary cortical neurons under low glucose-low oxygen. Behavioral tests assessed neurological deficits; immunofluorescence, immunohistochemistry, and Western-blot analyzed Fg and protein levels. Fluo-3/AM fluorescence measured free Ca2+ and ATP levels were gauged via specific assays and F560nm/F510nm ratio calculations. Mito-Tracker Green labeled mitochondria and immunoprecipitation studied protein interactions. Our comprehensive study revealed that Fg inhibited axonal regeneration post-MCAO as indicated by reduced GAP43 expression along with elevated free Ca2+, both suggesting an energy crisis. Fg impeded mitochondrial function and mediated impairment through the EGFR/Ca2+ axis by trans-activating EGFR via integrin αvβ3 interaction. These results indicate that the binding of Fg with integrin αvβ3 leads to the trans-activation of the EGFR/Ca2+ signaling axis thereby disrupting mitochondrial energy transport and axonal regeneration and exacerbating the detrimental effects of ischemic neuronal injury.

LncRNA Taurine Up-Regulated 1 Knockout Provides Neuroprotection in Ischemic Stroke Rats by Inhibiting Nuclear-Cytoplasmic Shuttling of HuR

Background: Long non-coding RNA taurine-upregulated gene 1 (TUG1) is involved in various cellular processes, but its role in cerebral ischemia–reperfusion injury remains unclear. This study investigated TUG1’s role in regulating the nucleocytoplasmic shuttling of human antigen R (HuR), a key apoptosis regulator under ischemic conditions. Methods: CRISPR-Cas9 technology was used to generate TUG1 knockout Sprague Dawley rats to assess TUG1’s impact on ischemic injury. The infarct area and neuronal apoptosis were evaluated using TUNEL, hematoxylin and eosin (HE), and TTC staining, while behavioral functions were assessed. Immunofluorescence staining with confocal microscopy was employed to examine TUG1-mediated HuR translocation and expression changes in the apoptosis-related proteins COX-2 and Bax. Results: TUG1 knockout rats showed significantly reduced cerebral infarct areas, decreased neuronal apoptosis, and improved neurological functions compared to controls. Immunofluorescence staining revealed that HuR translocation from the nucleus to the cytoplasm was inhibited, leading to decreased COX-2 and Bax expression levels. Conclusions: TUG1 knockout reduces ischemic damage and neuronal apoptosis by inhibiting HuR nucleocytoplasmic shuttling, making TUG1 a potential therapeutic target for ischemic stroke.

Intravenous Regeneration-associated Cell Transplantation Enhances Tissue Recovery in Mice with Acute Ischemic Stroke.

Previously, we reported that transplantation of regeneration-associated cells (RACs) via the ipsilateral external carotid artery reduced stroke volume in mice with permanent occlusion of the middle cerebral artery (MCA). However, intracarotid arterial transplantation is invasive and requires skill, and severe complications may occur, such as thromboembolism, infection, and decreased cerebral blood flow. This study aimed to investigate the efficacy of intravenous injection of RACs in reducing stroke volume and increasing anti-inflammatory and angiogenic factors in mice with focal cerebral ischemia. Mice with occluded MCAs received intravenous injections of phosphate-buffered saline (PBS) (control), low-dose RACs, or high-dose RACs. The proximal part of the left MCA was occluded to induce permanent focal ischemia. After 3 days, we administered PBS or low-dose (1 × 104 /50 µL) or high-dose RACs (1 × 105 /50 µL) through the tail vein and assessed the infarct volume on day 7. High-dose RACs significantly decreased infarct volume compared to PBS, whereas low-dose RACs showed no effect. The number of interleukin-10 (IL-10)-positive and vascular endothelial growth factor (VEGF)-positive cells in the peri-infarct area on day 7 was significantly higher in mice treated with low-dose and high-dose RACs than in the PBS control group. Intravenous injection of RACs can reduce ischemic stroke volume; however, a higher dose of RACs is required than the dose used in intraarterial transplantation. By assessing IL-10 and VEGF expression, the study sheds light on the underlying mechanisms of RAC therapy, revealing its potential anti-inflammatory and angiogenic properties in the treatment of cerebral ischemia.

Fecal microbiota transplantation alleviates neuronal Apoptosis, necroptosis and M1 polarization of microglia after ischemic stroke

ObjectiveThis study aims to delve into the mechanisms underlying the improvement of neurological function in rats with ischemic stroke through fecal microbiota transplantation.Methods: A total of fifty male Sprague-Dawley rats were categorized into three groups: sham surgery, model, and fecal transplantation. We assessed behavioral and pathological alterations in the rats using modified neurological function scoring and TTC staining. Additionally, Western blot and immunofluorescence techniques were employed to examine the expression levels of RIP1, RIP3, MLKL, p-MLKL, Bcl-2, Bax, and cleaved caspase-3 in neurons of ischemic brain tissue, while iNOS and Arg1 were analyzed to evaluate microglial polarization.Results: The fecal transplantation group exhibited a decline in neurological function score compared to the model group, accompanied by a reduction in infarct volume (P < 0.05). Relative to the sham surgery group, the model group displayed a significant increase in the expression levels of necroptosis-related proteins RIP1, RIP3, p-MLKL, apoptotic proteins Bax and cleaved caspase-3, and the M1 microglial cell marker iNOS in ischemic brain tissue, while Bcl-2 expression was notably decreased (P < 0.05). Conversely, compared to the model group, the fecal transplantation group demonstrated decreased expression levels of RIP1, RIP3, p-MLKL, Bax, cleaved caspase-3, and iNOS, along with increased expression of Bcl-2.Conclusion: Fecal microbiota transplantation presents a promising avenue for enhancing neurological function in rats with ischemic stroke by inhibiting neuronal apoptosis, necroptosis, and M1 polarization of microglial cells.

Clinical application of the modified Pullicino formula in endovascular thrombectomy in acute anterior circulation large cerebral infarction-A two-center retrospective study.

This study aimed to assess whether the modified Pullicino formula could be used as a screening indicator for measuring infarct volume before endovascular thrombectomy (EVT) and observe baseline factors affecting neurological recovery in patients with acute anterior circulation large-core cerebral infarction. The Pullicino formula × (1-22%) was applied to anterior circulation large cerebral infarctions with ASPECTS <6 to screen patients with infarct volumes of 70-150 mL. The outcomes were assessed by mRS score at 90 days, modified Treatment in Cerebral Ischemia (mTICI) score, symptomatic intracranial hemorrhage within 48 h, and death rate within 90 days. Significantly more patients in the EVT group with infarct volumes 70-150 mL had mRS ≤3 at 90 days than did the standard drug therapy (OR, 2.93; 95% CI, 1.08-7.89, p=0.03) and a significantly decreased mortality rate (OR, 0.36; 95% CI, 0.13-0.98; p=0.04), with 88.2% in patients with mTICI ≥2b. There was no significant difference in the intracranial hemorrhage. EVT (adjusted OR [aOR], 2.84; 95% CI, 1.15-7.01, p=0.02), infarct volume <150 mL (aOR, 3.47; 95% CI, 1.20-10.14, p=0.02), and intracranial atherosclerosis (aOR, 4.20; 95% CI, 1.24-14.04, p=0.02) were significantly associated with patient prognosis. Without commercial artificial intelligence software, the modified Pullicino formula can be used to calculate infarct volume and, in combination with ASPECTS <6, to select patients who may benefit from EVT.

The effects of Cordyceps polysaccharides on ischemic brain injury in rats via intervening with IL-23/IL-17 axis and the intestinal barrier

Cordyceps polysaccharide (CSP) has been shown to exhibit anti-inflammatory and antioxidant effects, with potential applications in ischemic stroke. This work is to explore the interventional potential of CSP in MCAO rats and the effects on the intestinal and cerebral IL-23/IL-17 axis. We conducted pharmacological experiments and mechanism exploration in MCAO rats. Our research showed that CSP improved the neurological function and cerebral pathological morphology, reduced cerebral infarction volume and water content in MCAO rats. We also found that CSP significantly decreased the IL-β, TNF-α and IL-6 in the ischemic brain and enhanced the ability of MCAO rats to resist oxidative stress. Additionally, CSP improved intestinal barrier, inhibited the activation of the TLR4/Myd88/NF-κβ signaling pathway and IL-23/IL-17 axis. The study results demonstrated the effectiveness of CSP in interfering with MCAO rats. The mechanism appears to be related to protecting the intestinal barrier and inhibiting the IL-23/IL-17 axis.

Basal Ganglia’s influence on awake test in carotid endarterectomy

BackgroundWhite matter changes (WMC) have been associated with the underlying presence of chronic cerebral ischemia, such as in carotid stenosis and age-related white matter changes (ARWMC). A low attenuation on computed tomography (CT) characterizes these alterations. Patients undergoing carotid endarterectomy (CEA) with severe WMC may be at increased risk of intraoperative neurologic deficits (IND) during carotid clamping. This study aims to determine the potential role of ARWMC as a predictor of IND during CEA with regional anesthesia (RA). MethodsPatients undergoing CEA under RA at a tertiary referral center, who presented with IND during CEA were prospectively and consecutively recruited between January 2011 and December 2023. The control group comprised the immediately consecutive patient who underwent the same procedure without IND. From this sample, patients with preoperative CT were selected and compared based on ARWMC score (≤ 1 and 2). Differences in demographics and comorbidities were assessed between the groups. A multivariable logistic regression was performed. ResultsOne hundred and twenty-one patients were enrolled. Patients with IND had a significantly higher ARWMC score in basal ganglia (ARWMC-BG ≥ 2) and posterior circulation disease was more frequent (27.8 %). No significant differences were observed in anatomical variations of the circle of Willis.For patients with ARWMC-BG ≥ 2, a significant burden of other comorbidities was associated, such as chronic kidney disease, coronary disease, and atrial fibrillation. After multivariable logistic regression analysis, ARWMC-BG score ≥ 2 was an independent risk factor for IND (aOR 3.472). ConclusionAn ARWMC-BG score above 2 predicts positive intraoperative “awake tests” in CEA with RA, constituting a reliable tool to stratify patients according to their risk of adverse events. However, larger prospective cohorts are needed to validate these findings and offer a better selection and management of this subset of patients.

Exploration the effective components of Gastrodia elata in improving cerebral ischemia reperfusion injury based on “Spectrum-effect” correlation and zebrafish verification experiment

BackgroundGastrodia elata (GE) has been widely used in clinical practice for many years with the functions of relieving stroke, suppressing liver Yang, dispelling wind and clearing collaterals. Our group's previous experimental studies have proved that GE has therapeutic effect on cerebral ischemia reperfusion injury (CIRI) (Ding et al., 2022). However, the active components of GE in treating CIRI remain unclear and require further research. PurposeThe purpose of this paper was to explore the potential effective components of GE improving CIRI based on the “Spectrum-effect” correlation. Zebrafish model was used for verification in vivo experimental. Materials and methodsFirst, the absorption components and metabolites of GE in rat serum were identified using ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF/MS). Second, pharmacodynamic indexes were determined by ELISA kit method, and the effect-time curve of each pharmacodynamic indexes was established. The potential compounds were screened using the statistical method of grey correlation between pharmacodynamic indicator and component response. Finally, the zebrafish CIRI model was successfully established, and the in vivo effect of the active components of GE was verified intuitively. Results45 chemical components were detected in GE. A total of 87 active components in serum of GE were identified including 25 prototype components and 62 metabolites. GE can improve CIRI by regulating the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), MDA levels and SOD levels. It was found that p-hydroxy benzaldehyde (PHB), p-hydroxybenzyl alcohol (PHBA) and gastrodin (GA) of GE were the possibly main active components by grey correlation statistics. The in vivo experiments of zebrafish model showed that PHB, PHBA, and GA have the ability to ameliorate cerebral thrombosis by regulation of oxidative stress and apoptosis. ConclusionsThe potential active components of GE on CIRI were initially excavated using UHPLC-Q-TOF-MS/MS, pharmacodynamics, and in vivo experiments of zebrafish model. It makes up for the disadvantages of separate research on chemical components and pharmacodynamics, and reflects the material basis of pharmacodynamics more objectively. It has provided theoretical basis for further quality evaluation and scientific foundation for rational drug using of GE in clinical.

Astrocyte-TREM2 alleviates brain injury by regulating reactive astrocyte states following ischemic stroke.

Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to confer strong neuroprotective effects in acute ischemic stroke (AIS). However, as the vast majority of research findings to date are based on its functions in microglia, the precise role of TREM2 in astrocytes after AIS is unknown. Here, both loss- and gain-of-function experiments were employed to investigate how astrocytic TREM2 influences the pathogenesis of AIS in vivo and in vitro. Our results demonstrated that cerebral ischemia triggered induction of TREM2 expression on reactive astrocytes following AIS. In addition, astrocyte-specific TREM2 knockout mice exhibited much greater brain injury than TREM2 flox/flox controls following AIS, as evidenced by increased cerebral infarct volume, neuronal apoptosis and neurological deficit, which was associated with an increased expression of pro-inflammatory molecule complement component 3 (C3) on reactive astrocytes and activation of microglia/macrophages but decreased expression of S100 calcium binding protein A10 (S100A10) and arginase1 (Arg1) on reactive astrocytes. Mechanistic analyses revealed that astrocytic TREM2 alleviated brain injury by inhibiting detrimental actions of reactive astrocytes but promoting their neuro- and glioprotective actions via the kruppel-like transcription factor-4-nuclear factor-κB axis. Together, this study provides novel evidence for a critical protective role of astrocyte-derived TREM2 in AIS and highlights a potential therapeutic target for the treatment of AIS.

Neovascularization as a Leading Mechanism of Intraplaque Hemorrhage and Carotid Plaque Destabilization: A Narrative Review.

Intraplaque neovascularization (IPN) is considered a leading mechanism causing carotid plaque destabilization. We provide an objective and comprehensive summary of the biology, imaging techniques, and treatment options related to carotid IPN. Plaque neovascularization has been reported to originate mainly from the adventitial vasa vasorum as a response to hypoxia. The leakage and rupture of neovessels lead to the formation of extravasations and foci of inflammation that destabilize the plaque. Vascular endothelial growth factor and its receptors are key regulators of neoangiogenesis. Neovascularization can be analyzed by advanced computed tomography and magnetic resonance imaging. The basic tools for the ultrasound assessment of IPN are contrast-enhanced ultrasound, superb microvascular imaging, and ultrasound molecular imaging. A promising direction of research seems to be the identification of patients with advanced plaque neovascularization. A simple test assessing low-velocity flow in the IPN can detect patients at risk of stroke before they experience rupture of defective neovessels and intracerebral embolism. In addition to surgical treatment, the stabilization of carotid atherosclerotic plaque can be supported pharmacologically. Statins have the best-documented role in this respect. The ideal moment of intensified therapeutic intervention in patients with previously stable carotid plaque is its increased neovascularization. However, the time frame in which intracerebral embolization may occur is unknown, and therapeutic intervention may be too late. The formation of deficient neovessels can currently be non-invasively evaluated with ultrasound. Superb microvascular imaging may change the clinical approach for asymptomatic patients at risk of cerebral ischemia.

Pharmacotherapy in SAH: Clinical Trial Lessons.

Subarachnoid Haemorrhage (SAH) is a medical emergency with potentially devastating outcomes. It is without doubt that over the past decades, there has been a radical change in the approach towards patients with SAH, both in terms of the surgical as well as of the pharmacological treatments offered. The present review aims to outline the principal data regarding the best practice in the pharmacotherapy of SAH, as well as to sum up the emerging evidence from the latest clinical trials. To date, nimodipine is the only evidence-based treatment of vasospasm. However, extensive research is currently underway to identify novel substances with magnesium sulphate, cilostazol, clazosentan and fasudil, demonstrating promising results. Antifibrinolytic therapy could help reduce mortality, and anticoagulants, in spite of their associated hazards, could actually reduce the incidence of delayed cerebral ischemia. The effectiveness of triple-H therapy has been challenged, yet evidence on the optimal regimen is still pending. Statins may benefit some patients by reducing the incidence of vasospasm and delayed ischemic events. As several clinical trials are underway, it is expected that in the years to come, more therapeutic options will be added to the attending physician's armamentarium.

Intraoperative neurophysiologic monitoring during cardiac surgery: an observational cohort study

ObjectiveTo evaluate the impact of intraoperative neuromonitoring (IONM) on stroke and operative mortality after coronary and/or valvular operations.MethodsThis was an observational study of coronary and/or valvular heart operations from 2010...

Lutein, a versatile carotenoid: Insight on neuroprotective potential and recent advances

BackgroundNeurodegenerative diseases (NDDs) are a diverse group of neurological disorders with progressive neuronal loss at specific brain regions, leading to impaired cognitive functioning, loss of neuroplasticity, severe neurological impairment, and dementia. The incidence of neurodegenerative diseases is increasing at an alarming rate with current treatments struggling to barely prolong the inevitable. The desperation to discover a therapeutic agent to treat neurodegenerative diseases and to aid in the process of healthy recovery has opened a gateway into natural pigments. HypothesisThe xanthophyll pigment lutein may bear the potential as a therapeutic agent against NDDs. ResultsLutein plays an important role in brain development, cognitive functioning, and improving neuroplasticity. In vitro and in vivo studies revealed the neuroprotective properties of lutein against NDDs such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and cerebral ischemia. The neuroprotective effect of lutein is evidenced by the reduction of free radicals and the simultaneous strengthening of the endogenous antioxidant systems by activating the NRF-2/ERK/AKT pathway. Further, it effectively suppressed mitochondrial aberrations, excitotoxicity, overaccumulation of metals, and its resultant complications. The immunomodulatory activity of lutein prevents neuroinflammation by hindering NF-κB nuclear translocation, regulation of NIK/IKK, PI3K/AKT, MAPK/ERK, JNK pathways, and ICAM-1 downregulation. Lutein also rescued the dysregulated cholinergic system and resolved memory defects. Along with its neuroprotective properties, lutein also improved neuroplasticity by enabling neurogenesis through increased GAP-43, NCAM, and BDNF levels. ConclusionLutein exhibits strong neuroprotective activities against various NDDs. Though the investigations are in the exploratory phase, this review presents the consolidation of scattered evidence of the neuroprotective properties of lutein and urges its further exploration in clinical studies.

Circle of Willis and Its Anatomical Relevance

The Circle of Willis is an arterial network located at the base of the brain, formed by the interconnection of the anterior, middle, and posterior cerebral arteries, along with the anterior and posterior communicating arteries. It connects the internal carotid arteries to the vertebral arteries, allowing the distribution of cerebral blood flow. Its significance lies in its ability to offer an alternative pathway in cases of arterial obstruction, helping to prevent cerebral ischemia. However, anatomical variations of this structure are common, and only 20% to 25% of the population has a "complete" or symmetrical configuration. Such variations can influence the risk of cerebrovascular diseases, such as stroke, as they may compromise the efficiency of the compensatory mechanism. These anatomical variations have a direct impact on the diagnosis and treatment of neurological conditions. The integrity of the Circle of Willis can influence the severity of symptoms in cases of ischemic strokes, as well as affect aneurysm formation and its clinical implications. Advances in imaging techniques, such as CT angiography and magnetic resonance imaging, have enabled more accurate diagnoses and the development of more effective treatments for conditions associated with the Circle of Willis, making its anatomical understanding essential for the prevention and management of cerebrovascular diseases.

Regional heterogeneity of cerebral blood flow immediately after the onset of ventricular pacing in anesthetized rats.

Selective distribution of cerebral blood flow (CBF) to vital brain regions likely occurs during rapid severe hypotension caused by tachyarrhythmia, but has not yet been demonstrated. In this study, we aimed to test the hypothesis that CBF is differentially preserved between brain regions depending on the degree of hypotension. In anesthetized rats, CBF was measured in the motor cortex (MC), medial prefrontal cortex, amygdala, thalamus, dorsal hypothalamus, hippocampus, ventral tegmental area, dorsolateral periaqueductal gray (dlPAG), and parabrachial nucleus (PB) by using laser-Doppler flowmetry. Ventricular pacing was performed for 30 s at 550-800 beats/min. The cerebrovascular CO2 response time and reactivity were evaluated during 5% CO2 exposure. During 1-4 s of ventricular pacing, mean arterial pressure (MAP) rapidly decreased, with minor changes in central venous and intracranial pressures. CBF was relatively well maintained in brain regions other than the MC (Ps ≤ 0.012) when moderate hypotension occurred (-34 mmHg ≤ ΔMAP ≤ -15 mmHg), whereas severe hypotension (-54 mmHg ≤ ΔMAP ≤ -35 mmHg) induced selective CBF distribution to regions other than the MC, thalamus, and dlPAG. The cerebrovascular CO2 response time/reactivity was rapid or high in the thalamus, dlPAG, and PB, which almost completely differed from the brain regions in which CBF was relatively maintained during pacing-induced severe hypotension. These results suggest that regional heterogeneity of CBF arises depending on the degree of tachyarrhythmia-induced hypotension. Clarifying the mechanisms and functions of CBF maintenance would be beneficial to syncope and cerebral ischemia management in patients with arrhythmia.

Galangin Regulates Astrocyte Phenotypes to Ameliorate Cerebral Ischemia-reperfusion Injury by Inhibiting the RhoA/ROCK/LIMK Pathway.

This study aimed to explore whether Galangin (Gal) could improve cerebral Ischemia- reperfusion (I/R) injury by regulating astrocytes, and clarify its potential molecular mechanism. An I/R injury model of rats was established using the Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R) method, followed by the administration of Gal (25, 50, 100 mg/kg) via gavage for 14 consecutive days. Besides, astrocytes were isolated from the rats to construct an Oxygen-Glucose Deprivation/Re-oxygenation (OGD/R) cell model, with treatments of Gal or the Ras homolog gene family member A (RhoA)/Rho-associated Coiled-coil containing protein Kinase (ROCK) inhibitor Y-27632. Subsequently, the severity of nerve injury was assessed using the modified Neurological Severity Score (mNSS) test; behavioral disorders in I/R rats were observed through the open field and ladder-climbing tests. Pathological damages and neuron survival in the peri-infarct zone were examined by hematoxylin and eosin staining and NeuN staining, respectively. Additionally, immunofluorescence staining was employed to determine astrocyte polarization and TUNEL staining was carried out to measure the level of cell apoptosis; also, western blot was performed to detect the expression of proteins related to the RhoA/ROCK/LIM domain Kinase (LIMK) pathway. Gal significantly ameliorated the neurological and motor dysfunctions caused by I/R in rats, reduced pathological damage in the peri-infarct zone, and promoted neuronal survival. Additionally, Gal increased the number of A2 astrocytes, while it decreased the number of A1 astrocytes. In vitro experiments revealed that the effect of Gal was consistent with that of Y-27632. Additionally, Gal significantly enhanced the survival of OGD/R cells, increased the number of A2 astrocytes, and inhibited the expression of proteins associated with the RhoA/ROCK pathway. Gal could reduce the level of apoptosis, promote the polarization of A2 astrocytes, and improve cerebral I/R injury, and its mechanism may be related to the inhibition of the RhoA/ROCK pathway.

Peripapillary vessels density is closely related to cerebral white matter hyperintensities: An OCTA study.

Chronic cerebral hypoperfusion triggers the development of white matter hyperintensities (WMHs), common in cerebral small vessel disease (CSVD). However, conventional imaging techniques cannot visualize cerebral small vessels. The retina, a direct extension of the central nervous system, has an unclear correlation with WMHs. This study employs Optical coherence tomographic angiography (OCTA) to investigate vascular changes in the retina and explore its correlation with WMHs, aiming to provide a new method for assessing perfusion in early ischemic brain WMHs. Forty-nine patients with WMHs were stratified into mild and moderate/severe WMHs groups based on MRI findings, utilizing the Fazekas and Scheltens scales. OCTA assessed fundus vessel microcirculation. Logistic regression analyzed the correlation between ocular fundus microcirculation and WMH severity and location. Additionally, ROC curves evaluated the diagnostic efficacy of each fundus vascular microcirculation index in determining WMH severity. After adjusting for multiple confounders, finding consistently indicated that the moderate/ severe WMHs group exhibited lower vessel density (VD) in the superior quadrant of the inner peripapillary region compared to the mild group [OR = 0.487, CI (0.255,0.929), p < 0.05]. ROC curves revealed that when combined with age, diabetes, and superior quadrant VD of the inner peripapillary region, specificity could be increased to 94.1%. Peripapillary vessel density correlates closely with the severity of cerebral WMHs. Early morphological changes due to chronic hypoperfusion may initiate from the inner layer of the optic disc, and OCTA could offer a novel method for evaluating blood perfusion in ischemic WMHs.

Perivascular Neutrophil Extracellular Traps Exacerbate Microvasospasm After Experimental Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) can lead to acute or delayed cerebral ischemia. Recent findings have revealed that spasm of microvessels, called microvasospasm, may contribute to SAH-related cerebral ischemia, and perivascular inflammation is considered important in the development of microvasospasms. However, owing to the difficulty in investigating the dynamics of vascular and perivascular events, little is known about the mechanisms underlying microvasospasms. We established an experimental system aiming to investigate the vascular and perivascular pathology of SAH by combining a SAH mouse model with intravital 2-photon imaging. SAH was induced by intracisternal blood injection, and the distribution of erythrocytes, neutrophil behavior, and morphological changes in the pial arterioles were analyzed over time by 2-photon microscopy imaging. To further explore the role of neutrophils and neutrophil extracellular traps (NETs) in microvasospasm, we performed neutrophil depletion by intraperitoneal administration of neutrophil-specific antibody or NETs removal by intracisternal administration of DNase. Erythrocytes were immediately distributed in the perivascular space of the arterioles after SAH induction; neutrophils intensively infiltrated the perivascular space within 2 days and subsequently showed NETosis; and pial arterioles in the same region developed pearl-string-like microvasospasms in the subacute phase. Neutrophil depletion significantly reduced the number of microvasospasms. Furthermore, the removal of perivascular NETs drastically reduced microvasospasms. By establishing a unique experimental system, we demonstrated that perivascular NETs could be a new therapeutic target for microvasospasms.

Novel Calcitonin Gene-Related Peptide (CGRP) Interfering Migraine Therapies and Stroke-A Review.

Migraine and stroke are neurological disorders with significant global prevalence and impact. Recent advances in migraine therapy have focused on the calcitonin gene-related peptide (CGRP) pathway. This review examines the shared pathomechanisms between migraine and stroke, with emphasis on the role of CGRP. We analyze the current literature on CGRP's functions in cerebrovascular regulation, edema formation, neuroinflammation, and neuroprotection. CGRP acts as a potent vasodilator and plays a crucial role in trigeminovascular activation during migraine attacks. In stroke, CGRP has demonstrated neuroprotective effects by improving collateral circulation and reducing ischemia-reperfusion injury. Concerns have been raised about the potential impact of CGRP inhibitors on stroke risk and outcomes. Studies in animals suggest that CGRP receptor antagonists may worsen cerebral ischemia by impairing collateral flow. We discuss the implications of these findings for the use of CGRP-targeting therapies in migraine patients, especially those at increased risk of stroke. Additionally, we explore the complex interplay between CGRP, endothelial function, and platelet activity in both conditions. This review highlights the need for further research to elucidate the long-term cerebrovascular safety of CGRP pathway inhibitors and to identify potential subgroups of migraine patients who may be at higher risk of adverse cerebrovascular events with these novel therapies.