Pathogenesis Of Ischemic Stroke Research Articles

Patent foramen ovale as a cause of cryptogenic ischemic stroke

A patent foramen ovale from an anatomical and physiological point of view is a normal communication between the atria, which is present in utero and allows oxygenated placental blood to reach the fetal arterial circulation. With incomplete postpartum fusion of the primary and secondary septa, a patent foramen ovale is formed. In the last two decades, clinical interest in the problem of the patent foramen ovale is dictated by the fact that its role in the development of such clinical syndromes as ischemic stroke, myocardial infarction, pulmonary embolism, migraine and decompression sickness of divers has been established, as well as the introduction of endovascular techniques for endovascular transcatheter closure of the atrial septal defect. It was found that the frequency of patent foramen ovale detection in patients with cryptogenic stroke is on average 2 times higher than in patients with an established cause of ischemic stroke and ranges from 40% to 50%.Aim of study. Raising awareness of neurologists about the causes, pathogenetic mechanisms of development, methods of diagnosis and treatment of ischemic stroke in patients with patent foramen ovale.Material and methods. To achieve this goal, the results of scientific research devoted to patent foramen ovale as a risk factor for cryptogenic stroke were analyzed. The literature search was carried out in electronic search engines Scopus, eLibrary, PubMed using the keywords: «ischemic stroke», «cryptogenic stroke», «patent foramen ovale», «pathogenesis of ischemic stroke». Scientific articles published between 1878 and 2021 were selected for analysis. 31% of the analyzed works are not older than 5 years.Conclusion. The patent foramen ovale is etiologically associated with cryptogenic stroke. Possible mechanisms of ischemic stroke in patent foramen ovale patients include in situ thrombosis, paradoxical embolism, and atrial arrhythmias. Transcatheter endovascular closure of patent foramen ovale with anatomical signs of a high risk of cerebrovascular events in combination with antiplatelet therapy are indicated for patients with cryptogenic stroke aged 18 to 60 years as an optimal means of secondary prevention of ischemic stroke.

AKG Attenuates Cerebral Ischemia-Reperfusion Injury through c-Fos/IL-10/Stat3 Signaling Pathway.

Inflammation is dominant in the pathogenesis of ischemic stroke (IS). Alpha-ketoglutarate (AKG), according to previous studies, has demonstrated a variety of pharmacological effects such as antioxidation and inhibitive inflammation activities. However, whether AKG ameliorates cerebral ischemic injury, as well as the underlying molecular events, is still unclear. Therefore, the effect and underlying mechanisms of AKG on ischemic brain injury should be identified. The study established a cerebral ischemia-reperfusion (I/R) model in mice as well as an oxygen-glucose deprivation/reperfusion (OGD/R) model in SH-SY5Y cells, respectively. It was observed that AKG markedly suppressed infarction volume and neuronal injuries and improved the neurological score in vivo. Moreover, AKG reduced the inflammatory response and lowered the expression of proinflammatory cytokines. In vitro, AKG treatment strongly inhibited OGD/R-induced neuronal injury and the proinflammatory factors. It was also found that the increased SOD and GSH levels, as well as the lower ROS levels, showed that AKG reduced oxidative stress in OGD/R-treated SY-SY5Y cells. Mechanistically, AKG largely promoted IL-10 expression in ischemic brain injury and OGD/R-induced neuronal injury. Furthermore, IL-10 silencing neutralized the protective effect of AKG on inflammation. Notably, it was discovered that AKG could upregulate IL-10 expression by promoting the translocation of c-Fos from the cytoplasm to the nucleus. The results indicated that AKG demonstrated neuroprotection on cerebral ischemia while inhibiting inflammation through c-Fos/IL-10/stat3 pathway.

Analyzing Corin-BNP-NEP Protein Pathway Revealing Differential Mechanisms in AF-Related Ischemic Stroke and No AF-Related Ischemic Stroke.

BackgroundThe incidence of atrial fibrillation (AF)-related stroke increases with aging. Natriuretic peptides (NPs) family, including Corin-B type natriuretic peptide (BNP)-neprilysin (NEP) protein levels increased with age and are risk markers of cardiovascular and cerebrovascular diseases, such as AF and cardioembolic stroke. Aging is also linked to epigenetics, specifically DNA methylation. However, only a few studies have investigated the effect of DNA methylation on the NP system. Thus, the present study aimed to investigate whether the Corin-BNP-NEP protein pathway is involved in the pathogenesis of AF-stroke and CpG methylation in the promoter region of the Corin protein gene has an effect on AF-related ischemic stroke.MethodsA total of 82 patients hospitalized with acute ischemic strokes were enrolled in this study. The differences in clinical information were compared between the AF-stroke (n = 37) and no AF-stroke groups (n = 45). Plasma-soluble Corin and NEP were detected using an ELISA kit. CpG methylation in the promoter region of the gene was assessed by a next-generation sequencing-based bisulfite sequencing polymerase chain reaction (BSP).Results(1) Patients in AF-stroke were older, had higher initial NIHSS score, 90-day mRs, higher D2-dimer, INR, and APTT, and low TG, TC, and HbA1c (all p < 0.05). (2) Serum levels of Corin and BNP in the AF-stroke group were significantly higher than that in the no AF-stroke group (p < 0.05). No significant difference was detected in the serum levels of NEP between the two groups. (3) The levels of CpG methylation in the promoter region of the Corin protein gene in the AF-stroke group was significantly lower than that in the no AF-stroke group (p < 0.05). The CpG sites with maximal methylation differences between the two groups were CORIN:678, CORIN:682, CORIN:694, and CORIN:700.ConclusionThe current findings raise the possibility that the Corin–BNP–NEP protein pathway may be involved in the pathogenesis of AF-related ischemic stroke. Deficient CpG methylation in the promoter region of the Corin protein gene is associated with AF-related ischemic stroke.

Longitudinal variation of circulating Inc-ITSN1-2: A novel biomarker reflecting disease severity, inflammation, recurrence, and death risk in acute ischemic stroke patients.

BackgroundLong noncoding RNA intersectin 1–2 (lnc‐ITSN1‐2) regulates inflammation and neuronal apoptosis; meanwhile, the latter two factors participate in the pathogenesis of acute ischemic stroke (AIS). Therefore, this study detected lnc‐ITSN1‐2 at multiple time points, aiming to explore its longitudinal variation and clinical value in the management of AIS patients.MethodsThe current study enrolled 102 AIS patients, then detected their lnc‐ITSN1‐2 in peripheral blood mononuclear cell (PBMC) at baseline (D0), day (D)1, D3, D7, month (M)1, M3, M6, and year (Y)1 after admission using RT‐qPCR. Additionally, lnc‐ITSN1‐2 in PBMC of 50 controls was also detected.ResultsLnc‐ITSN1‐2 was up‐regulated in AIS patients than that in controls (p < 0.001). Lnc‐ITSN1‐2 positively associated with NIHSS score, TNF‐α, and IL‐17A (all p < 0.050) but was not linked with IL‐6 (p = 0.093) in AIS patients. Notably, lnc‐ITSN1‐2 was gradually increased from D0 to D3; while it switched to decrease from D3 to Y1 in AIS patients. Lnc‐ITSN1‐2 disclosed similar longitudinal variation during 1 year in non‐recurrent (p < 0.001), recurrent (p = 0.001), and survived patients (p < 0.001), while the variation of lnc‐ITSN1‐2 in died patients was not obvious (p = 0.132). More importantly, lnc‐ITSN1‐2 at D0, D3, D7, M1, M3, M6, and Y1 was higher in recurrent AIS patients than that in non‐recurrent AIS patients (all p < 0.050); moreover, lnc‐ITSN1‐2 at D3, D7, M1, M3, and M6 was up‐regulated in died AIS patients than AIS survivors (all p < 0.050).ConclusionThe dynamic variation of Inc‐ITSN1‐2 could serve as a biomarker reflecting disease severity, inflammatory cytokines, recurrence, and death risk in AIS patients.

Single-Cell RNA-Sequencing Analyses Revealed Heterogeneity and Dynamic Changes of Metabolic Pathways in Astrocytes at the Acute Phase of Ischemic Stroke.

Astrocyte plays important roles in the pathogenesis of ischemic stroke and reperfusion injury. They intensively participate in the energy metabolism of the brain, while their heterogeneity and function after ischemic stroke remain controversial. By employing single-cell sequencing of mice cortex at 12 h after transient middle cerebral artery occlusion (tMCAO) and comparing with the similar published datasets of 24h after tMCAO, we uncover the cellular phenotypes and dynamic change of astrocytes at the acute phase of ischemic stroke. In this study, we separately identified 3 major subtypes of astrocytes at the 12 h-tMCAO-system and 24 h-tMCAO-system, indicated the significant differences in the expression of genes and metabolic pathways in the astrocytes between the two time nodes after ischemic stroke, and detected the major change in the energy metabolism. These results provided a comprehensive understanding of the characteristic changes of astrocytes after ischemic stroke and explored the potential astrocytic targets for neuroprotection.

Intertwined Relation between the Endoplasmic Reticulum and Mitochondria in Ischemic Stroke.

In ischemic stroke (IS), accumulation of the misfolded proteins in the endoplasmic reticulum (ER) and mitochondria-induced oxidative stress (OS) has been identified as the indispensable inducers of secondary brain injury. With the increasing recognition of an association between ER stress and OS with ischemic stroke and with the improved understanding of the underlying molecular mechanism, novel targets for drug therapy and new strategies for therapeutic interventions are surfacing. This review discusses the molecular mechanism underlying ER stress and OS response as both causes and consequences of ischemic stroke. We also summarize the latest advances in understanding the importance of ER stress and OS in the pathogenesis of ischemic stroke and discuss potential strategies and clinical trials explicitly aiming to restore mitochondria and ER dynamics after IS.

Longitudinal Variations of CDC42 in Patients With Acute Ischemic Stroke During 3-Year Period: Correlation With CD4+ T Cells, Disease Severity, and Prognosis.

ObjectiveCell division cycle 42 (CDC42) modulates CD4+ T-cell differentiation, blood lipids, and neuronal apoptosis and is involved in the pathogenesis of acute ischemic stroke (AIS); however, the clinical role of CDC42 in AIS remains unanswered. This study aimed to evaluate the expression of CDC42 in a 3-year follow-up and its correlation with disease severity, T helper (Th)1/2/17 cells, and the prognosis in patients with AIS.MethodsBlood CDC42 was detected in 143 patients with AIS at multiple time points during the 3-year follow-up period and in 70 controls at admission by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, blood Th1, Th2, and Th17 cells and their secreted cytokines (interferon-γ (IFN-γ), interleukin-4 (IL-4), and interleukin-17A (IL-17A)) in patients with AIS were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively.ResultsCompared with controls (p < 0.001), CDC42 was reduced in patients with AIS. CDC42 was negatively correlated with the National Institutes of Health Stroke Scale (NIHSS) score (p < 0.001), whereas, in patients with AIS (all p < 0.050), it was positively associated with Th2 cells and IL-4 but negatively correlated with Th17 cells and IL-17A. CDC42 was decreased from admission to 3 days and gradually increased from 3 days to 3 years in patients with AIS (P<0.001). In a 3-year follow-up, 24 patients with AIS recurred and 8 patients died. On the 3rd day, 7th day, 1st month, 3rd month, 6th month, 1st year, 2nd year, and 3rd year, CDC42 was decreased in recurrent patients than that in non-recurrent patients (all p < 0.050). CDC42 at 7 days (p = 0.033) and 3 months (p = 0.023) was declined in reported deceased patients than in survived patients.ConclusionCDC42 is used as a biomarker to constantly monitor disease progression and recurrence risk of patients with AIS.

β-Caryophyllene suppresses ferroptosis induced by cerebral ischemia reperfusion via activation of the NRF2/HO-1 signaling pathway in MCAO/R rats

BackgroundIschemic stroke is a complex brain disease regulated by several cell death processes, including apoptosis, autophagy, and ferroptosis. β-Caryophyllene (BCP), a natural bicyclic sesquiterpene abundantly found in essential oils, has been demonstrated to have potential pharmacological benefits in many diseases, including ischemic stroke. PurposeThis research was to determine the existence of ferroptosis in the pathogenesis of acute ischemic stroke and investigate whether BCP can inhibit ferroptosis to improve cerebral ischemia injury by activating the NRF2/HO-1 signaling pathway in rats. MethodsFirst, we verified ferroptosis by assessing proferroptotic changes after middle cerebral artery occlusion reperfusion (MCAO/R), along with protein and lipid peroxidation levels. Then male rats were divided randomly into Sham, MCAO/R, ML385 (NRF2-specific inhibitor) and BCP groups. The effects of BCP on cerebral injury were detected by the modified neurological severity score, TTC staining, and hematoxylin-eosin staining. We conducted western blotting analyzes of proteins, including those involved in ferroptosis and related signaling pathways. To demonstrate the neuroprotective effect of BCP in vitro, primary astrocytes were pretreated with different concentrations of BCP (10, 20, and 40 μM) for 24 h before oxygen-glucose deprivation/re-oxygenation (ODG/R). ResultsWe concluded that ferroptosis was engaged in the process of I/R-induced neurological damage, implying that this novel type of cell death might provide new therapeutic options for the clinical treatment of ischemic stroke. In vivo study proved that BCP improved neurological scores, infarct volume, and pathological features after MCAO/R. We demonstrated that BCP evidently enhanced NRF2 nuclear translocation, activated the NRF2/HO-1 pathway, which protected against ferroptosis. In vitro investigation revealed the same results. BCP decreased OGD/R-induced ROS generation and iron accumulation. Furthermore, the neuroprotective effects of BCP were reversed by the NRF2 inhibitor ML385. ConclusionOur results indicated the critical role of ferroptosis in cerebral I/R injury. For the first time, we showed that the significant neuroprotective effects of BCP in attenuating ischemic stroke injury are correlated with ferroptosis regulation, and its mechanism is associated with activation of the NRF2/HO-1 axis.

The correlation of lncRNA SNHG16 with inflammatory cytokines, adhesion molecules, disease severity, and prognosis in acute ischemic stroke patients.

BackgroundLong non‐coding RNA small nucleolar RNA host gene 16 (lncRNA SNHG16) is involved in the pathogenesis of acute ischemic stroke (AIS) through the regulation of brain endothelial cell viability, inflammation, atherosclerotic plaque formation, and neural apoptosis. This study aimed to evaluate the prognostic value of lncRNA SNHG16 in AIS patients.MethodsNewly diagnosed AIS patients (N = 120) were serially recruited. Their lncRNA SNHG16 expressions in peripheral blood mononuclear cells (PBMCs) were detected by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR); serum inflammatory cytokines and adhesion molecules were determined using enzyme‐linked immunosorbent assay (ELISA). The accumulating recurrence‐free survival (RFS) and overall survival (OS) were analyzed. Moreover, controls (N = 60) were recruited and their lncRNA SNHG16 expressions in PBMCs were detected.ResultsLncRNA SNHG16 was declined in AIS patients compared to controls (p < 0.001). Moreover, lncRNA SNHG16 was not related to any comorbidities in AIS patients (all p > 0.05). Interestingly, lncRNA SNHG16 was negatively related to tumor necrosis factor alpha (TNF‐α) (p < 0.001), interleukin 6 (IL‐6) (p = 0.013), and intracellular cell adhesion molecule‐1 (ICAM‐1) (p = 0.024), while positively correlated with interleukin 10 (IL‐10) (p = 0.022) in AIS patients. Besides, lncRNA SNHG16 was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score in AIS patients (p = 0.003). During the follow‐up period, in 14 (11.7%) patients occurred recurrence and 5 (4.2%) patients died. Unexpectedly, lncRNA SNHG16 was not associated with accumulating RFS (p = 0.103) or OS (p = 0.150) in AIS patients.ConclusionLncRNA SNHG16 relates to lower inflammatory cytokines, adhesion molecules, and milder disease severity, but fails to predict prognosis in AIS patients.

The Influence of Gut Dysbiosis in the Pathogenesis and Management of Ischemic Stroke.

Recent research on the gut microbiome has revealed the influence of gut microbiota (GM) on ischemic stroke pathogenesis and treatment outcomes. Alterations in the diversity, abundance, and functions of the gut microbiome, termed gut dysbiosis, results in dysregulated gut–brain signaling, which induces intestinal barrier changes, endotoxemia, systemic inflammation, and infection, affecting post-stroke outcomes. Gut–brain interactions are bidirectional, and the signals from the gut to the brain are mediated by microbially derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs); bacterial components, such as lipopolysaccharide (LPS); immune cells, such as T helper cells; and bacterial translocation via hormonal, immune, and neural pathways. Ischemic stroke affects gut microbial composition via neural and hypothalamic–pituitary–adrenal (HPA) pathways, which can contribute to post-stroke outcomes. Experimental and clinical studies have demonstrated that the restoration of the gut microbiome usually improves stroke treatment outcomes by regulating metabolic, immune, and inflammatory responses via the gut–brain axis (GBA). Therefore, restoring healthy microbial ecology in the gut may be a key therapeutic target for the effective management and treatment of ischemic stroke.

Circulating Non-coding RNAs as Potential Biomarkers for Ischemic Stroke: A Systematic Review.

Recent studies have demonstrated that dysregulated non-coding RNAs (ncRNAs) are involved in the pathogenesis of ischemic stroke (IS), including neuroinflammation, apoptosis, atherosclerosis, and angiogenesis. However, discrepant results make it difficult to apply ncRNAs to clinical practice. Therefore, we performed a meta-analysis to evaluate and elucidate the diagnostic value of ncRNAs in IS. We searched the literature in four databases-PubMed, Web of Science, EMBASE, and the Cochrane Library-up to December 31, 2020, to identify the relationship between differentially expressed ncRNAs and IS. Pooled sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the diagnostic performance of ncRNAs. Fifteen studies on microRNAs (miRNAs) including 1687 IS patients and eight studies on long non-coding RNAs (lncRNAs) including 741 IS patients were included in our study. Estimates of the identification efficiency of miRNAs from the 15 studies were as follows: 0.76 (95% CI: 0.67-0.84) for sensitivity (SEN), 0.83 (95% CI: 0.77-0.88) for specificity (SPE), 4.5 (95% CI: 3.4-6.1) for PLR, 0.29 (95% CI: 0.20-0.40) for NLR, and 16 (95% CI: 10-26) for DOR. The area under the curve (AUC) of the summary receiver operator characteristic (SROC) curve showed diagnostic accuracy of 0.87 (95% CI: 0.84-0.90); thus the diagnostic value of all the miRNAs was moderate. In addition, the results for lncRNAs were as follows: 0.73 (95% CI: 0.69-0.77) for SEN, 0.75 (95% CI: 0.70-0.79) for SPE, 2.9 (95% CI: 2.4-3.4) for PLR, 0.36 (95% CI: 0.31-0.42) for NLR, 8 (95% CI: 6-11) for DOR, 0.80 (95% CI: 0.76-0.83) for AUC, and a moderate diagnostic value. Our study revealed that blood-circulating ncRNAs could be a moderately effective candidate biomarker for the diagnosis of IS. Furthermore, the combined lncRNAs showed more accurate diagnostic properties than single lncRNAs, and some single miRNAs (e.g., miR-107) showed better diagnostic performance, which may contribute to IS clinical practice.

Prognostic Role of the Platelet-Lymphocyte Ratio in Acute Ischemic Stroke Patients Undergoing Reperfusion Therapy: A Meta-Analysis.

BackgroundBoth inflammation and thrombotic/hemostatic mechanisms may play a role in acute ischemic stroke (AIS) pathogenesis, and a biomarker, such as the platelet-to-lymphocyte ratio (PLR), considering both mechanisms may be of clinical utility.ObjectivesThis meta-analysis sought to examine the effect of PLR on functional outcomes, early neurological changes, bleeding complications, mortality, and adverse outcomes in AIS patients treated with reperfusion therapy (RT).DesignSystematic Review and Meta-AnalysisData Sources and MethodsIndividual studies were retrieved from the PubMed/Medline, EMBASE and Cochrane databases. References thereof were also consulted. Data were extracted using a standardised data sheet, and systematic reviews and meta-analyses on the association of admission (pre-RT) or delayed (post-RT) PLR with defined clinical and safety outcomes were conducted. In the case of multiple delayed PLR timepoints, the timepoint closest to 24 hours was selected.ResultsEighteen studies (n=4878) were identified for the systematic review, of which 14 (n=4413) were included in the meta-analyses. PLR collected at admission was significantly negatively associated with 90-day good functional outcomes (SMD=−.32; 95% CI = −.58 to −.05; P=.020; z=−2.328), as was PLR collected at delayed timepoints (SMD=−.43; 95% CI = −.54 to −.32; P<.0001; z=−7.454). PLR at delayed timepoints was also significantly negatively associated with ENI (SMD=−.18; 95% CI = −.29 to −.08; P=.001. Conversely, the study suggested that a higher PLR at delayed timepoints may be associated with radiological bleeding and mortality. The results varied based on the type of RT administered.ConclusionsA higher PLR is associated with worse outcomes after stroke in terms of morbidity, mortality, and safety outcomes after stroke.

Liraglutide Ameliorates Cerebral Ischemia in Mice via Antipyroptotic Pathways.

It was recently shown that pyroptosis, an inflammatory form of programmed cell death, is critically involved in the pathogenesis of ischemic stroke. Liraglutide (Lg) is a novel long-acting analog of glucagon-like peptide-1 that has potential protective effects against stroke. However, the relationship between Lg and pyroptosis in the brain is not well defined. In this study, we found that injection of Lg significantly improved the recovery of motor function, increased cerebral blood flow and ameliorated cerebral damage in a mouse model of focal cerebral cortical ischemia. Our results revealed that Lg treatment significantly reduced the levels of NLRP3, Caspase1, IL-1β and the pore-forming protein gasdermin D in microglial cells in vitro, suggesting that the neuroprotective effect of Lg may be achieved through the inhibition of pyroptosis. Furthermore, by using a specific inhibitor of NOD-like receptor protein 3 (NLRP3), we confirmed that the antipyroptotic mechanism of Lg may be mediated by NLRP3 in vivo. Our present study unveils a novel neuroprotective mechanism through which Lg alleviates ischemia by exerting NLRP3-dependent antipyroptotic effects.

Dyslipidemia in Acute Non-cardioembolic Ischemic Stroke Patients at a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Acute ischemic stroke is the second most common cause of death after ischemic heart disease worldwide and Nepal's top five diseases based on Disability-Adjusted Life Years. Dyslipidemia is a major risk factor for coronary heart disease but has an unclear role in the pathogenesis of ischemic stroke. The objective of this study was to find the prevalence of dyslipidemia in acute non-cardioembolic ischemic stroke patients at a tertiary care centre. A descriptive cross-sectional study was conducted among 76 patients with acute noncardioembolic ischemic stroke admitted in the Neuromedicine unit of a tertiary care centre from August 2017 to July 2018. Ethical approval was obtained from the Institutional Review Committee of the same institute (Reference number: 478/2020). Patients underwent baseline investigations, including fasting lipid profile and Computed Tomography Scan/Magnetic Resonance Imaging head. Data were analysed using Statistical Package for the Social Sciences version 21.0. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data. The prevalence of dyslipidemia among the acute non-cardioembolic ischemic stroke patients was 35 (46.05%) (35.05-57.05 at 95% Confidence Interval) where high total cholesterol was diagnosed in 11 (31.43%), high triglycerides in 25 (71.43%), high low-density-lipoprotein in 10 (28.57%), and low high-density-lipoprotein in 11 (31.43%) patients. The prevalence of dyslipidemia among acute non-cardioembolic ischemic stroke patients at our tertiary care centre is higher than the similar studies done in similar settings. cardioembolic stroke; dyslipidemia; ischemic stroke; lipid; lipoprotein.

Abstract P237: Matrix Metalloproteinases (MMPs) And Risk Of Incident Hemorrhagic And Ischemic Stroke: The Atherosclerosis Risk In Communities Study (ARIC)

Introduction: Matrix metalloproteinases (MMPs), belong to a family of zinc-dependent endopeptidases, have been found to induce stroke through its role in extracellular matrix destruction. MMPs also affect the stroke prognosis by disrupting blood brain barrier during stroke. Genetic association studies suggest that MMPs are involved in the pathogenesis of both ischemic and hemorrhagic stroke. Hypothesis: High MMP-2, MMP-9 and ratio of MMP-9/TIMP-1 are associated with higher risk of ischemic and hemorrhagic stroke. Method: After exclusion of missing data and prevalent stroke, 11,393 ARIC participants were followed from midlife (visit 3; 1993-1995) and 4,924 participants followed from late life (visit 5; 2011-2013) to 2019. Plasma levels of MMPs were measured by SOMAscan version 4 assay. Stroke cases were reviewed and adjudicated by neurologists. We used Cox models to examine the relationship between MMPs and stroke risk. Result: Mean age of participants were 60±5.7 at visit 3 and 76±5.2 at visit 5. At visit 3 55% were female and 21% Black. A total of 1,013 ischemic and 127 hemorrhagic strokes occurred over 22.34 years of follow-up for the visit 3 analysis and 319 ischemic and 30 hemorrhagic strokes over 7.24 years for the visit 5 analysis. A significant and positive association was detected for MMP-2 at visit 3 baseline for hemorrhagic stroke (HR (95% CI): 2.28 (1.14-4.57)) and at visit 5 baseline with ischemic stroke (1.65 (1.08-2.53)), after covariate adjustment. No associations were observed with MMP-9 and TIMP-1. Conclusion: Results of MMP-2 indicate a possible relationship with MMPs and stroke subtypes, but were not consistent. Though no significance were found for MMP-9 and TIMP-1, their direction of associations with stroke was consistent with the hypothesis.

THE STATE OF SOME INDICATORS OF HEMOSTASIS IN RELATIVELY HEALTHY PEOPLE AND PATIENTS WITH ISCHEMIC STROKE, TAKING INTO ACCOUNT GENDER DIFFERENCES

Goal. To study some indicators of hemostasis in a comparative aspect in patients with ischemic stroke and healthy people, taking into account gender differences.&#x0D; Materials and methods. In the course of the study, the hemostasis indices of 160 people were studied. All the examined were divided into two subgroups, the first consisted of 100 donors, 50 men and women each, who did not have acute and chronic diseases. The second group included the study of analogical indicators in 60 people, 30 men and women, with an established diagnosis of acute ischemic cerebral circulation disorder.&#x0D; Results. As the results show, differences in hemostasis indicators were found, taking into account gender differences, and disorders in the hemostasis system play an important role in the pathogenesis of ischemic stroke. The obtained results suggest that as a result of the development of endothelial tissue dysfunction, the level of endothelin increased, which led to pronounced vascular spasm and increased procoagulant activity of the blood.&#x0D; Conclusion. Based on the conducted research, it was found that in men and women at the time of admission with ischemic stroke, in comparison with the results obtained from donors without established pathology, changes in red blood parameters and rheological properties of blood are observed in the blood. It should be noted that in the group of female patients, changes in the rheological properties of blood were less pronounced than in the group of male patients.

Review of the Elemental Status in Blood Serum in Patients with Ischemic Stroke

The study of the elemental status in the modern paradigm of medical diagnostics occupies an increasingly large niche due to the possible use of trace elements as possible predictors of cerebrovascular pathologies. Moreover, the great importance of the elemental component in the main enzymatic systems of metabolism allows us to consider them also as a therapeutic target. There are many mechanisms in the pathophysiology of stroke development, each of which, in one way or another, is mediated through the interaction of regulatory proteins with trace elements as cofactors. Therefore, it is necessary to pay close attention to elemental homeostasis in the focus of ischemic pathologies. Aim. Systematization of the known pathogenetic effects of the most metabolic homeostasis important elements on the course of stroke, both contributing factors to earlier rehabilitation and minimal neurological deficit after the ischemic event itself, and factors aggravating the recovery process and leading to serious neurological consequences. This pursues not only a prognostic goal to determine the severity of ischemia or to identify risk groups with certain shifts in elemental constants, but also the therapeutic one — to replace the falling functions of the dropping metabolic agents, as happens with the elements involved in antioxidant systems. It is also necessary to develop a methodology for stopping the excess of nerve cells mediating excitotoxicity with calcium ions, which closes the vicious circle of vascular necrosis with additional destruction of the nervous tissue. Conclusion. The conclusions that we can summarize quite convincingly indicate a significant contribution of the elemental status to the pathogenesis of ischemic stroke. Dysregulation of the elemental component can force the damaging effect of ischemia on brain cells. At the same time, many elements show a surplus during an ischemic event: Li, I, Mn, Zn, As, Se, Pb, Sr, Ni, however, not all of the presented elements negatively affect the course of stroke, since an increase in the level of some metals may be compensatory in nature, and for their further applicability as diagnostic and therapeutic agents, similar analytics are required.

Neuroprotective effects of alisol A 24-acetate on cerebral ischaemia\u2013reperfusion injury are mediated by regulating the PI3K/AKT pathway

BackgroundNeuroinflammation and apoptosis are involved in the pathogenesis of ischaemic stroke. Alisol A 24-acetate (24A) exerts a strong inhibitory effect on inflammation and cell apoptosis. The neuroprotective effect of 24A on global cerebral ischaemia/reperfusion (GCI/R) injury remains unclear.MethodsGCI/R mice were used to investigate the neuroprotective effect of 24A. Modified neurological deficit scores, Morris water maze and object recognition tests were used to evaluate behaviours. Metabolism in brain regions was detected using magnetic resonance spectroscopy (MRS), and changes in microglia, astrocytes and neurons were detected. Inflammation and apoptosis were measured.ResultsThe results showed that 24A suppressed neurological deficits scores and improved GCI/R induced cognitive dysfunction. It was also observed that 24A could alleviate neuroinflammation, which manifested as 24A inhibited microglia and astrocytes proliferation, downregulated the expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) in the GCI/R mice brain. The apoptosis of neurons reduced, and dendritic spines of hippocampal neurons increased in the presence of 24A. In addition, 24A could up-regulate the expression of phosphorylated phosphoinositide 3-kinases (p-PI3K) and phosphorylated protein kinase B (p-AKT) in GCI/R mice brain, and all the morphological, neurological, and biochemical changes of 24A treatment were abolished by the application of PI3K/AKT pathway inhibitor LY294002.ConclusionsTaken together, our study indicated that 24A alleviated GCI/R injury by inhibiting neuroinflammation and apoptosis through the regulation of the PI3K/AKT pathway.

Post COVID-19 Vaccination-Associated Neurological Complications.

PurposeNeurological sequelae after COVID-19 vaccination are rare. We investigated the possible pathogenesis behind the development of neurological complications within a short period after Saudi residents received a COVID-19 vaccine.Patients and MethodsWe evaluated 18 patients who recently received a COVID-19 vaccine (Comirnaty and Vaxzevria vaccines) and presented with neurological complications to the Saudi German Hospitals in Jeddah, Saudi Arabia. Neurologists assessed the patients’ clinical presentation, radiological investigations, and laboratory findings.ResultsThree patients who received the first dose of the Vaxzevria vaccine experienced severe cerebral venous thrombosis, two of them were complicated by intracranial hemorrhage. Their laboratory investigations showed very high d-dimers and severe thrombocytopenia, which have been linked to higher mortality and poor outcome. Ischemic stroke occurred in eight cases (44.4%) with a predominance in older male patients. Three patients presented with seizures, two had optic neuritis. Guillain–Barré syndrome (GBS) and Miller Fisher syndrome (MFS) occurred in two male patients following vaccination with Comirnaty.ConclusionNeurological complications after COVID-19 vaccinations are very rare, and only a few cases have been reported worldwide. The shared pathophysiological basis between COVID-19 viral infection and COVID-19 vaccines stands behind the very rare neurological complications resulting from the hypercoagulable state triggered by the general inflammatory condition. We suspect some differences in the pathogenesis of ischemic stroke caused by COVID-19 infection and COVID-19 vaccines, which render COVID-19 vaccine-associated ischemic stroke more responsive to treatment. To date, no definitive association between the vaccine and GBS has been proven by any strong evidence, but it has recently been added as a very rare side effect of the Janssen COVID-19 vaccine. No possible links of Miller Fisher syndrome to COVID-19 vaccines have been reported before the one reported in this study.

Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway after ischemia

Ethnopharmacological relevanceRehmannioside A is derived from Rehmannia glutinosa Libosch, which is widely used as an important ingredient in diverse traditional Chinese medicines to treat diseases caused by “kidney deficiency” such as cerebral arteriosclerosis, aging-related stroke and dementia in China. Recent studies have proved that Rehmannia glutinosa Libosch and Rehmannioside A can improve memory capability and recover nerve damage. Aim of the studyTo investigate the effect of Rehmannioside A on cognitive impairment after ischemia in rats and SH-SY5Y cells, and further evaluate the anti-oxidative and anti-ferroptosis mechanisms. Materials and methodsDifferentially expressed proteins (DEPs) in patients after cerebral ischemic stroke were revealed by a RayBio protein array. Cognitive impairment model was established by middle cerebral artery occlusion and reperfusion (MCAO) 14 days in rats. Rehmannioside A was administered intraperitoneally injection at dose of 80 mg/kg. The SH-SY5Y cells were exposed to H2O2 for 24 h and treated with Rehmannioside A (80 μM) for 24 h. The neuroprotecion of Rehmannioside A were evaluated by infarct volume (TTC), neurological defects (Garcia score) and learning memory (Morris water maze test) in vivo, and cell viability (CCK-8 or LDH) in vitro. Superoxide dismutase (SOD), malondialdehyde (MDA) and myeloperoxidase (MPO) activity of rats, glutathione (GSH), oxidized glutathione (GSSG) and nicotinamide adenine dinucleotide phosphate (NADPH) of cells were detected by biochemical assay. Intracellular reactive oxygen species (ROS) were measured by DCFH-DA assay. Myeloperoxidase (MPO), PI3 kinase (PI3K), p-PI3K, Akt, p-Akt, heme oxygenase-1 (HO-1), nuclear factor-E2-related factor 2 (Nrf2), SLC7A11, glutathione peroxidase 4 (GPX4) of the cerebral cortex in rats or SH-SY5Y cells were examined by western blotting. ResultsCompared with model group, the cognitive impairment and neurological deficits of Rehmannioside A group were significantly improved, and the cerebral infarction was reduced in MCAO rats. Moreover, the cell viability obviously increased and the H2O2-induced toxicity was reduced in Rehmannioside A group. Further research indicated that the expression of p-PI3K, p-Akt, nuclear Nrf2, HO-1 and SLC7A11 in Rehmannioside A group was significantly higher than model group. ConclusionRehmannioside A has neuroprotection effect and improves cognitive impairment after cerebral ischemia by inhibiting ferroptosis and activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway. These findings provide valuable insight into the pathogenesis and therapeutic target of ischemic stroke.