Acute Cerebral Ischemia Research Articles

Omentin-1 Suppressed Inflammation by NLRP3 through AMPK Function

This experiment investigated the biological roles of Omentin-1 in cerebral vessels of acute cerebral ischemia (ACI). The expressions of Omentin-1 in mouse model or patients with ACI were down-regulated. Moreover, Omentin-1 was negatively correlated with NIHSS score or serum IL-1β expression in patients undergoing intravenous thrombolysis for ACI. Omentin-1 was positively correlated with Barthel index in patients undergoing intravenous thrombolysis for ACI. In the mouse model or the in-vitro model, Omentin-1 mitigated inflammation factors. Additionally, in the in-vitro model of ACI, overexpression of Omentin-1 induced AMPK/ NLRP3 signaling pathway. Down-regulation of Omentin-1 also inhibited AMPK/ NLRP3 signaling pathway. Taken together, Omentin-1 suppressed ACI in the ACI model through inhibiting inflammation, which might serve as a potential treatment strategies of cardiovascular and cerebrovascular diseases in ACI.

Effective high-density lipoprotein cholesterol is associated with carotid intima-media thickness and vascular events after acute ischemic stroke

Background and aimsEffective high density lipoprotein cholesterol (HDL-C) is a measure of HDL functionality. We evaluated if HDL-C is associated with carotid intima-media thickness (cIMT) and incident major adverse cardiovascular events (MACE) in patients with acute ischemic stroke from two prospective cohort studies. MethodsIn the MARK-STROKE cohort, 299 patients with acute ischemic stroke or TIA were included. Outcome was available in 219 patients during a median follow-up of 294 days. In CIRCULAS, 382 acute ischemic stroke patients were included and a 90-day follow-up was available in 213 patients. HDL-C was calculated based on symmetric dimethylarginine (SDMA) and HDL cholesterol concentrations. Main outcome was incident MACE (death, stroke, and myocardial infarction) and the main measure was cIMT. ResultsIn both studies, HDL-C was inversely associated with cIMT in linear regression analysis adjusted for age, sex and creatinine. In MARK-STROKE, the adjusted hazard for MACE was significantly reduced for patients with one unit increase (mg/dL) of HDL-C (hazard ratio 0.95 [95% confidence interval (CI): 0.92, 0.99]). In the CIRCULAS cohort, stroke patients with higher HDL-C had less incident MACE during 90 days of follow-up (odds ratio: 0.97 [95% CI: 0.94, 0.99] for one unit increase). Neither SDMA nor HDL cholesterol predicted outcome. ConclusionsOur findings imply a protective role of biologically effective HDL after acute cerebral ischemia for secondary events and emphasize the relevance of lipoprotein functionality in these patients.

Repeated intravenous infusion of mesenchymal stem cells for enhanced functional recovery in a rat model of chronic cerebral ischemia.

Stroke is a major cause of long-term disability, and there are few effective treatments that improve function in patients during the chronic phase of stroke. Previous research has shown that single systemic infusion of mesenchymal stem cells (MSCs) improves motor function in acute and chronic cerebral ischemia models in rats. A possible mechanism that could explain such an event includes the enhanced neural connections between cerebral hemispheres that contribute to therapeutic effects. In the present study, repeated infusions (3 times at weekly intervals) of MSCs were administered in a rat model of chronic stroke to determine if multiple dosing facilitated plasticity in neural connections. The authors induced middle cerebral artery occlusion (MCAO) in rats and, 8 weeks thereafter, used them as a chronic stroke model. The rats with MCAO were randomized and intravenously infused with vehicle only (vehicle group); with MSCs at week 8 (single administration: MSC-1 group); or with MSCs at weeks 8, 9, and 10 (3 times, repeated administration: MSC-3 group) via femoral veins. Ischemic lesion volume and behavioral performance were examined. Fifteen weeks after induction of MCAO, the thickness of the corpus callosum (CC) was determined using Nissl staining. Immunohistochemical analysis of the CC was performed using anti-neurofilament antibody. Interhemispheric connections through the CC were assessed ex vivo by diffusion tensor imaging. Motor recovery was better in the MSC-3 group than in the MSC-1 group. In each group, there was no change in the ischemic volume before and after infusion. However, both thickness and optical density of neurofilament staining in the CC were greater in the MSC-3 group, followed by the MSC-1 group, and then the vehicle group. The increased thickness and optical density of neurofilament in the CC correlated with motor function at 15 weeks following induction of MCAO. Preserved neural tracts that ran through interhemispheric connections via the CC were also more extensive in the MSC-3 group, followed by the MSC-1 group and then the vehicle group, as observed ex vivo using diffusion tensor imaging. These results indicate that repeated systemic administration of MSCs over 3 weeks resulted in greater functional improvement as compared to single administration and/or vehicle infusion. In addition, administration of MSCs is associated with promotion of interhemispheric connectivity through the CC in the chronic phase of cerebral infarction.

Coexistence of SARS-CoV-2 and cerebrovascular diseases: does COVID-19 positivity trigger cerebrovascular pathologies?

The objectives of this study were to determine the prevalence of cerebrovascular diseases caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and to assess the pharmacological agents used in such cases as reported in the literature. Patient files were retrospectively scanned to determine the prevalence of neurological symptoms of the central nervous system (headache, dizziness, lack of smell and taste, numbness in arms and legs, change in consciousness, muscle weakness, loss of urine and stool control) and cerebrovascular diseases (ischemic cerebrovascular diseases, cerebral venous sinus thrombosis, intracerebral hemorrhage, subarachnoid/subdural hemorrhage) in 2019 novel coronavirus (2019-nCoV) disease (COVID-19) cases (n = 20,099). The diagnostic laboratory, radiology examinations and treatments applied to these cases were recorded. The data from studies presenting cerebrovascular diseases associated with SARS-Cov-2, which constituted 0.035% of all cases, were systematically evaluated from electronic databases. During the treatment of cerebrovascular diseases, it was discovered that high doses of enoxaparin sodium anti-Xa are combined with apixaban or acetylsalicylic acid or clopidogrel or piracetam, and mannitol, in addition to SARS-CoV-2 treatment modalities. While neurological symptoms of the central nervous system are uncommon in cases of SARS-CoV-2 infection, cerebrovascular diseases are far less common, according to the findings of this study. Acute cerebral ischemia was discovered to be the most common cerebrovascular disease associated with SARS-CoV-2. The mortality rate increases with the association between SARS-CoV-2 and cerebrovascular disease.

Development and Evaluation of Novel Metformin Derivative Metformin Threonate for Brain Ischemia Treatment.

Epidemiologic data reveal that diabetes patients taking metformin exhibit lower incidence of stroke and better functional outcomes during post-stroke neurologic recovery. We previously demonstrated that chronic post-ischemic administration of metformin improved functional recovery in experimental cerebral ischemia. However, few beneficial effects of metformin on the acute phase of cerebral ischemia were reported either in experimental animals or in stroke patients, which limits the application of metformin in stroke. We hypothesized that slow cellular uptake of metformin hydrochloride may contribute to the lack of efficacy in acute stroke. We recently developed and patented a novel metformin derivative, metformin threonate (SHY-01). Pharmacokinetic profile in vivo and in cultured cells revealed that metformin is more rapidly uptaken and accumulated from SHY-01 than metformin hydrochloride. Accordingly, SHY-01 treatment exhibited more potent and rapid activation of AMP-activated protein kinase (AMPK). Furthermore, SHY-01 elicited a stronger inhibition of microglia activation and more potent neuroprotection when compared to metformin hydrochloride. SHY-01 administration also had superior beneficial effects on neurologic functional recovery in experimental stroke and offered strong protection against acute cerebral ischemia with reduced infarct volume and mortality, as well as the improved sensorimotor and cognitive functions in rats. Collectively, these results indicated that SHY-01 had an improved pharmacokinetic and pharmacological profile and produced more potent protective effects on acute stroke and long-term neurological damage. We propose that SHY-01 is a very promising therapeutic candidate for cerebral ischemic stroke.

Three-dimensional arterial spin labeling and diffusion kurtosis imaging in evaluating perfusion and infarct area size in acute cerebral ischemia.

BACKGROUNDEarly thrombolytic therapy is crucial to treat acute cerebral infarction, especially since the onset of thrombolytic therapy takes 1-6 h. Therefore, early diagnosis and evaluation of cerebral infarction is important.AIMTo investigate the diagnostic value of magnetic resonance multi-delay three-dimensional arterial spin labeling (3DASL) and diffusion kurtosis imaging (DKI) in evaluating the perfusion and infarct area size in patients with acute cerebral ischemia.METHODSEighty-four patients who experienced acute cerebral ischemia from March 2019 to February 2021 were included. All patients in the acute stage underwent magnetic resonance-based examination, and the data were processed by the system’s own software. The apparent diffusion coefficient (ADC), average diffusion coefficient (MD), axial diffusion (AD), radial diffusion (RD), average kurtosis (MK), radial kurtosis (fairly RK), axial kurtosis (AK), and perfusion parameters post-labeling delays (PLD) in the focal area and its corresponding area were compared. The correlation between the lesion area of cerebral infarction under MK and MD and T2-weighted imaging (T2WI) was analyzed.RESULTSThe DKI parameters of focal and control areas in the study subjects were compared. The ADC, MD, AD, and RD values in the lesion area were significantly lower than those in the control area. The MK, RK, and AK values in the lesion area were significantly higher than those in the control area. The MK/MD value in the infarct lesions was used to determine the matching situation. MK/MD < 5 mm was considered matching and MK/MD ≥ 5 mm was considered mismatching. PLD1.5s and PLD2.5s perfusion parameters in the central, peripheral, and control areas of the infarct lesions in MK/MD-matched and -unmatched patients were not significantly different. PLD1.5s and PLD2.5s perfusion parameter values in the central area of the infarct lesions in MK/MD-matched and -unmatched patients were significantly lower than those in peripheral and control areas. The MK and MD maps showed a lesion area of 20.08 ± 5.74 cm2 and 22.09 ± 5.58 cm2, respectively. T2WI showed a lesion area of 19.76 ± 5.02 cm2. There were no significant differences in the cerebral infarction lesion areas measured using the three methods. MK, MD, and T2WI showed a good correlation.CONCLUSIONDKI parameters showed significant difference between the focal and control areas in patients with acute ischemic cerebral infarction. 3DASL can effectively determine the changes in perfusion levels in the lesion area. There was a high correlation between the area of the infarct lesions diagnosed by DKI and T2WI.

Normobaric hyperoxia plays a neuroprotective role after cerebral ischemia by maintaining the redox homeostasis and the level of connexin43 in astrocytes.

IntroductionAcute cerebral ischemia is caused by an insufficient blood supply to brain tissue. Oxygen therapy, which is able to aid diffusion to reach the ischemic region, has been regarded as a possible treatment for cerebral ischemia. Recent animal and pilot clinical studies have reported that normobaric hyperoxia (NBO) showed neuroprotective effects if started soon after the onset of stroke. However, little is known about the role and mechanism of NBO treatment in astrocytes. Connexin43, one of the main gap junction proteins in astrocytes, is extremely sensitive to hypoxia and oxidative stress after cerebral ischemia.AimsIn the present study, we used sutures to develop an ischemia/reperfusion model in rats to mimic clinical recanalization and investigated the role of connexin43 in NBO‐treated stroke rats, as well as the underlying mechanism of NBO therapy.ResultsNormobaric hyperoxia treatment maintained the homeostasis of oxidoreductases: glutathione peroxidase 4 (GPX4) and NADPH oxidase 4 (two important oxidoreductases) and rescued the ischemia/reperfusion‐induced downregulation of connexin43 protein in astrocytes. Furthermore, NBO treatment attenuated cerebral ischemia‐induced cytochrome c release from mitochondria and was involved in neuroprotective effects by regulating the GPX4 and connexin43 pathway, using Ferrostatin‐1 (an activator of GPX4) or Gap27 (an inhibitor of connexin43).ConclusionsThis study showed the neuroprotective effects of NBO treatment by reducing oxidative stress and maintaining the level of connexin43 in astrocytes, which could be used for the clinical treatment of ischemic stroke.

The Clinical Impact of Methotrexate-Induced Stroke-Like Neurotoxicity in Paediatric Departments: An Italian Multi-Centre Case-Series.

IntroductionStroke-like syndrome (SLS) is a rare subacute neurological complication of intrathecal or high-dose (≥500 mg) Methotrexate (MTX) administration. Its clinical features, evoking acute cerebral ischaemia with fluctuating course symptoms and a possible spontaneous resolution, have elicited interest among the scientific community. However, many issues are still open on the underlying pathogenesis, clinical, and therapeutic management and long-term outcome.Materials and MethodsWe retrospectively analyzed clinical, radiological and laboratory records of all patients diagnosed with SLS between 2011 and 2021 at 4 National referral centers for Pediatric Onco-Hematology. Patients with a latency period that was longer than 3 weeks between the last MTX administration of MTX and SLS onset were excluded from the analysis, as were those with unclear etiologies. We assessed symptom severity using a dedicated arbitrary scoring system. Eleven patients were included in the study.ResultsThe underlying disease was acute lymphoblastic leukemia type B in 10/11 patients, while fibroblastic osteosarcoma was present in a single subject. The median age at diagnosis was 11 years (range 4–34), and 64% of the patients were women. Symptoms occurred after a mean of 9.45 days (± 0.75) since the last MTX administration and lasted between 1 and 96 h. Clinical features included hemiplegia and/or cranial nerves palsy, paraesthesia, movement or speech disorders, and seizure. All patients underwent neuroimaging studies (CT and/or MRI) and EEG. The scoring system revealed an average of 4.9 points (± 2.3), with a median of 5 points (maximum 20 points). We detected a linear correlation between the severity of the disease and age in male patients.ConclusionsSLS is a rare, well-characterized complication of MTX administration. Despite the small sample, we have been able to confirm some of the previous findings in literature. We also identified a linear correlation between age and severity of the disease, which could improve the future clinical management.

The Novel lncRNA ENST00000530525 Affects ANO1, Contributing to Blood-Brain Barrier Injury in Cultured hCMEC/D3 Cells Under OGD/R Conditions.

Ischemic stroke (IS) is a major neurological disease with high fatality and residual disability burdens. Long noncoding RNAs (lncRNAs) have been found to play an important role in IS. However, the roles and significance of most lncRNAs in IS are still unknown. This study was performed to identify differentially expressed (DE) lncRNAs using a lncRNA microarray in whole blood samples of patients suffering from acute cerebral ischemia. Bioinformatics analyses, including GO, KEGG pathway enrichment analysis, and proximity to putative stroke risk location analysis were performed. The novel lncRNA, ENST00000530525, significantly decreased after IS. Furthermore, we evaluated lncRNA ENST00000530525 expression in cultured hCMEC/D3 cells under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions using fluorescent in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (RT–qPCR) analysis. To investigate the function of lncRNA ENST00000530525, its over-expression (OE) and negative control (NC) plasmids were transfected into hCMEC/D3 cells, and cell viability was detected by a cell counting kit-8 (CCK-8) assay after OGD/R. LncRNA ENST00000530525 and ANO1 expression were investigated using RT–qPCR and immunofluorescence. For blood–brain barrier (BBB) permeability, FITC-dextran transendothelial permeability assay and tight junction (TJ) protein immunofluorescence assays were performed. There were 3352 DE lncRNAs in the blood samples of acute IS patients. The validation results were consistent with the gene chip data. The GO and KEGG results showed that these lncRNAs were mainly related to oxygen and glucose metabolism, leukocyte transendothelial migration, mitophagy and cellular senescence. Among these, lncRNA ENST00000530525 was the most highly downregulated lncRNA and it was mapped within the IS-associated gene anoctamin-1 (ANO1). We further found that lncRNA ENST00000530525 was downregulated in hCMEC/D3 cells under 4 h OGD and 20 h reoxygenation (OGD4/R20) conditions. Upregulating lncRNA ENST00000530525 by plasmid transfection decreased cell viability while increasing ANO1 expression and it contributed to BBB injury in hCMEC/D3 cells after OGD4/R20. The lncRNA ENST00000530525 might play deleterious roles in post-stroke pathogenesis. These results show that some DE lncRNAs in humans participate through characteristic roles in post-stroke pathogenesis; thus, the roles and significance of some novel lncRNAs in IS warrant further study.

Concept of 5P-medicine for prevention of acute cerebral ischemia in women

The objective. To evaluate the effectiveness of the 5P-model for the prevention of acute cerebral ischemia in Dagestan women.Materials and methods. The prospective study included 35 women permanently residing in Dagestan. The mean age was 66.46 ± 10.9 years. Each participant of the study was individually interviewed and examined clinically, neurologically, an additional examination included: complete blood test, biochemical blood test, coagulation test, molecular genetic study for 11 candidate gene mutations significant for the occurrence of ischemic stroke, electrocardiography, neuroimaging.Results. By analyzing the results of the study, individual background conditions that predispose to the occurrence of ischemic stroke were established. The results of the examination were explained to each participant, there were given the recommendations on lifestyle modification, a diet was prescribed and the necessary therapy was selected. In the process of dynamic observation for 4 years the observed group had no episodes of acute cerebrovascular accident.Conclusions. The study confirms the effectiveness of the use of the 5P-model for the prevention of acute cerebral ischemia in women Dagestan and declare a positive experience of its application.

Strokes in children

Introduction and purpose A stroke is a group of neurological symptoms that develops when blood flow to the brain is stopped suddenly. Stroke is relatively rare in the group of pediatric patients. The incidence is estimated at 2.5 cases per 100,000 children per year. Mortality is up to 4%. Long-term consequences and complications concern more than half of the patients. Brief description of the state of knowledge The etiopathogenesis of stroke in children is diverse. The main risk factors are congenital heart disease, vascular damage, metabolic diseases and infections. The symptoms of a stroke depend on the location and extent of the ischemic changes. In children they may initially be uncharacteristic. The most common are headaches, vomiting, convulsions, disturbed consciousness, and hemiparesis. The gold standard in cerebral ischemia imaging is brain magnetic resonance angiography (MRA). In treatment controlling vital parameters plays an important role. Treatment includes anti-aggregating and anticoagulant drugs. It is possible to transfuze blood or surgical treatment. Complications of stroke in children are diversify and depend on a lot of factors. These include movement disorders, cognitive functions impairment, tension headaches and difficulty with expression and fluency of speech. Conclusion A stroke is a life-threatening condition that requires immediate treatment. It can have uncharacteristic symptoms in children. Acute cerebral ischemia in children carries the risk of developing long-term, severe complications. Pediatric patients with a history of acute cerebral ischemia should be under the constant care of specialized treatment and rehabilitation centers, which will enable patients to function independently among their peers.

β-Actin: An Emerging Biomarker in Ischemic Stroke.

At present, the diagnosis of ischemic stroke mainly depends on neuroimaging technology, but it still has many limitations. Therefore, it is very important to find new biomarkers of ischemic stroke. Recently, β-actin has attracted extensive attention as a biomarker of a variety of cancers. Although several recent studies have been investigating its role in ischemic stroke and other cerebrovascular diseases, the understanding of this emerging biomarker in neurology is still limited. We examined human and preclinical studies to gain a comprehensive understanding of the literature on the subject. Most relevant literatures focus on preclinical research, and pay more attention to the role of β-actin in the process of cerebral ischemia, but some recent literatures reported that in human studies, serum β-actin increased significantly in the early stage of acute cerebral ischemia. This review will investigate the basic biology of β-actin, pay attention to the potential role of serum β-actin as an early diagnostic blood biomarker of ischemic stroke, and explore its potential mechanism in ischemic stroke and new strategies for stroke treatment in the future.

Beyond the Golden Hour: Treating Acute Stroke in the Platinum 30 Minutes.

To emphasize treatment speed for time-sensitive conditions, emergency medicine has developed not only the concept of the golden hour, but also the platinum half-hour. Patients with acute stroke treated within the first half-hour of onset have not been previously characterized. In this cohort study, we analyzed patients enrolled in the FAST-MAG (Field Administration of Stroke Therapy-Magnesium) trial, testing paramedic prehospital start of neuroprotective agent ≤2 hours of onset. The features of all acute cerebral ischemia, and intracranial hemorrhage patients with treatment starting at ≤30 m of last known well were compared with later-treated patients. Among 1680 patients, 203 (12.1%) received study agents within 30 minutes of last known well. Among platinum half-hour patients, median onset-to-treatment time was 28 minutes (interquartile range, 25-30), and final diagnoses were acute cerebral ischemia in 71.8% (ischemic stroke, 61.5%, TIA 10.3%); intracranial hemorrhage in 26.1%; and mimic in 2.5%. Clinical features among platinum half-hour patients were largely similar to later-treated patients and included age 69 (interquartile range, 57-79), 44.8% women, prehospital Los Angeles Motor Scale median 4 (3-5), and early-postarrival National Institutes of Health Stroke Scale deficit 8 (interquartile range, 3-18). Platinum half-hour acute cerebral ischemia patients did have more severe prehospital motor deficits and younger age; platinum half-hour intracranial hemorrhage patients had more severe motor deficits, were more often female, and less often of Hispanic ethnicity. Outcomes at 3 m in platinum half-hour patients were comparable to later-treated patients and included freedom-from-disability (modified Rankin Scale score, 0-1) in 35.5%, functional independence (modified Rankin Scale score, 0-2) in 53.2%, and mortality in 17.7%. Prehospital initiation permits treatment start within the platinum half-hour after last known well in a substantial proportion of acute ischemic and hemorrhagic stroke patients, accounting for more than 1 in 10 enrolled in a multicenter trial. Hyperacute platinum half-hour patients were largely similar to later-treated patients and are an attainable target for treatment in prehospital stroke trials.

Distribution of amyloid-β precursor protein-immunoreactive axons differs according to the severity of cerebral ischemia in autopsy brains.

Amyloid-β precursor protein (APP) immunohistochemistry has been used to detect axonal injury in forensic neuropathology. However, axonal injury caused by cerebral ischemia has not been investigated by APP immunohistochemistry in detail. In particular, it is unknown if there is a correlation between the prognosis of cerebral ischemia and the distribution of axonal injury detected by APP immunohistochemistry. To address this issue, we compared the distribution of APP-immunoreactive axons in autopsy brains including lesions of acute phase of cerebral infarction in the territory of the middle cerebral artery (MCA) or internal carotid artery (ICA) with the degree of severity. The presence or absence of a midline shift was used as an indicator of the severity of cerebral ischemia. We identified a difference in the distribution of APP-immunoreactive axons between cases with and without a midline shift. In both the groups, APP-immunoreactive axons were detected at the margin of the ischemic lesions; however, only in cases with a midline shift, intense APP-immunoreactive axons were also found in areas other than the MCA and ICA territories, including the white matter of the cerebral hemispheres ipsilateral and contralateral to the ischemic lesions. This distribution was different from that of acute global cerebral ischemia cases reported previously. Our results indicate that the distribution of APP-immunoreactive axons differs according to the severity and type of cerebral ischemia, suggesting that the distribution of APP-immunoreactive axons is associated with the prognosis of cerebral ischemia.

Acute Cerebral Ischemia Increases a Set of Brain-Specific miRNAs in Serum Small Extracellular Vesicles.

Small extracellular vesicles (sEVs) miRNAs are promising diagnosis and prognosis biomarkers for ischemic stroke (IS). This study aimed to determine the impact of IS on the serum sEVs miRNA profile of IS patients and a transient middle cerebral artery occlusion (tMCAO) mouse model. Small RNAseq was used to define the serum sEVs miRNA profile in IS patients and healthy controls (HC), and tMCAO mice and sham controls. Among the 1,444 and 1,373 miRNAs identified in human and mouse serum sEVs, the expression of 424 and 37 miRNAs was significantly altered in the IS patients and tMCAO mice, respectively (| Log2FC| ≥ 1, p < 0.01). Notably, five of the top 25 upregulated miRNAs in IS patients were brain-specific or enriched, including hsa-miR-9-3p, hsa-miR-124-3p, hsa-miR-143-3p, hsa-miR-98-5p, and hsa-miR-93-5p. Upregulation of these four miRNAs was further validated by qPCR. Nine of the 20 upregulated miRNAs in tMCAO mice were also brain-specific or enriched miRNAs. Temporal analysis indicated that the dynamics of mmu-miR-9-5p, mmu-miR-124-3p, mmu-miR-129-5p, and mmu-miR-433-3p were closely correlated with the evolution of ischemic brain injury, as their expression increased at 0.5 days after the onset of ischemia, peaked at day 1 or 3, and returned to normal levels at day 7 and 14. Notably, with the exceptions of mmu-miR-128-3p, the expression of the other eight miRNAs in the mouse serum sEVs was unaffected in the lipopolysaccharide (LPS)-induced neuroinflammation model. Together, in this study, we provided a comprehensive view of the influences of IS on the serum sEVs miRNA profile of IS patients and tMCAO mice and demonstrated the increment of a set of brain-specific miRNAs in serum sEVs after acute cerebral ischemia, which could be promising candidates directly reflecting the ischemic brain injury.

An Optimal Animal Model of Ischemic Stroke Established by Digital Subtraction Angiography-Guided Autologous Thrombi in Cynomolgus Monkeys.

ObjectiveIschemic stroke seriously threatens human health, characterized by the high rates of incidence, disability, and death. Developing a reliable animal model that mimics most of the features of stroke is critical for pathological studies and clinical research. In this study, we aimed to establish and examine a model of middle cerebral artery occlusion (MCAO) guided by digital subtraction angiography (DSA) in cynomolgus monkeys.Materials and MethodsIn this study, 15 adult male cynomolgus monkeys were enrolled. Under the guidance of DSA, a MCAO model was established by injecting an autologous venous clot into the middle cerebral artery (MCA) via femoral artery catheter. Thrombolytic therapy with alteplase (rt-PA) was given to eight of these monkeys at 3 h after the occlusion. Blood test and imaging examination, such as computed tomography angiography (CTA), CT perfusion (CTP), brain magnetic resonance imaging (MRI), and brain magnetic resonance angiography (MRA), were performed after the operation to identify the post-infarction changes. The behavioral performance of cynomolgus monkeys was continuously observed for 7 days after operation. The animals were eunthanized on the 8th day after operation, and then the brain tissues of monkeys were taken for triphenyltetrazolium chloride (TTC) staining.ResultsAmong the 15 cynomolgus monkeys, 12 of them were successfully modeled, as confirmed by the imaging findings and staining assessment. One monkey died of brain hernia resulted from intracranial hemorrhage confirmed by necropsy. DSA, CTA, and MRA indicated the presence of an arterial occlusion. CTP and MRI showed acute focal cerebral ischemia. TTC staining revealed infarct lesions formed in the brain tissues.ConclusionOur study may provide an optimal non-human primate model for an in-depth study of the pathogenesis and treatment of focal cerebral ischemia.

The attenuation effect of potassium 2-(1-hydroxypentyl)-benzoate in a mouse model of diabetes-associated cognitive decline: The protein expression in the brain.

Aims dl‐PHPB (potassium 2‐(1‐hydroxypentyl)‐benzoate) has been shown to have neuroprotective effects against acute cerebral ischemia, vascular dementia, and Alzheimer's disease. The aim of this study was to investigate the effects of dl‐PHPB on memory deficits and preliminarily explore the underlying molecular mechanism.MethodsBlood glucose and behavioral performance were evaluated in the KK‐Ay diabetic mouse model before and after dl‐PHPB administration. Two‐dimensional difference gel electrophoresis (2D‐DIGE)‐based proteomics was used to identify differentially expressed proteins in brain tissue. Western blotting was used to study the molecular mechanism of the related signaling pathways.ResultsThree‐month‐old KK‐Ay mice were given 150 mg/kg dl‐PHPB by oral gavage for 2 months, which produced no effect on the level of serum glucose. In the Morris water maze test, KK‐Ay mice treated with dl‐PHPB showed significant improvements in spatial learning and memory deficits compared with vehicle‐treated KK‐Ay mice. Additionally, we performed 2D‐DIGE to compare brain proteomes of 5‐month KK‐Ay mice treated with and without dl‐PHPB. We found 14 altered proteins in the cortex and 11 in the hippocampus; two of the 25 altered proteins and another four proteins that were identified in a previous study on KK‐Ay mice were then validated by western blot to further confirm whether dl‐PHPB can reverse the expression levels of these proteins. The phosphoinositide 3‐kinase/protein kinase B/glycogen synthase kinase‐3β (PI3K/Akt/GSK‐3β) signaling pathway was also changed in KK‐Ay mice and dl‐PHPB treatment could reverse it.ConclusionsThese results indicate that dl‐PHPB may play a potential role in diabetes‐associated cognitive impairment through PI3K/Akt/GSK‐3β signaling pathway and the differentially expressed proteins may become putative therapeutic targets.

Сomorbidity of coronary artery disease and its significance in predicting the results of coronary artery bypass grafting

The review presents an analysis of the scientific literature on comorbidity of coronary artery disease (CAD) and assessment of its impact on the results of coronary artery bypass grafting (CABG). Arterial hypertension (AH), chronic obstructive pulmonary disease (COPD), metabolic syndrome (MS), and diabetes mellitus (DM) have been shown to be the most common comorbidities in CAD patients. Clinical manifestations of cardiovascular comorbidities also include atrial fibrillation, acute cerebral ischemia, atherosclerosis of carotid and lower limb arteries, and chronic heart failure.Concomitant COPD doubles the risk of postoperative complications after CABG and reduces the 10-year survival rate in patients to 30%. In CAD patients with MS, the risk of postoperative mortality increases by 1.4 times, and the 5-year survival rate decreases by 3 times. Diabetes significantly worsens the long-term survival of patients after CABG and is an independent predictor of acute cardiovascular events after revascularization in the long term. The presence of various comorbidities in CAD patients requires a personalized approach to managing the risks of adverse outcomes after CABG and introduction of modern artificial intelligence (AI) technologies into clinical practice, which significantly increase the accuracy of prognosis.

Role of Neutrophil-Lymphocyte Ratio in the Prognosis of Acute Ischaemic Stroke After Reperfusion Therapy: A Systematic Review and Meta-analysis.

BackgroundInflammation may mediate response to acute reperfusion therapy (RT) in acute cerebral ischaemia. Neutrophil-lymphocyte ratio (NLR), an inflammatory biomarker, may play an important role in acute ischaemic stroke (AIS) prognostication.ObjectiveThis meta-analysis sought to examine the effect of NLR on functional outcomes, mortality and adverse outcomes in AIS patients receiving RT.MethodsIndividual studies were retrieved from PubMed/Medline, EMBASE and Cochrane databases. Data were extracted using a standardised data sheet and meta-analysis on association of admission (pre-RT) or delayed (post-RT) NLR with clinical/safety outcomes after RT was conducted.ResultsThirty-five studies (n = 10 308) were identified for the systematic review with 27 (n = 8537) included in the meta-analyses. Lower admission NLR was associated with good functional outcomes (GFOs), defined as 3-month modified Rankin scale (mRS) 0–2 (SMD = −.46; 95% CI = −.62 to −.29; P < .0001), mRS 0–1 (SMD = −.44; 95% CI = −.66 to −.22; P < .0001) and early neurological improvement (ENI) (SMD = −.55; 95 %CI = −.84 to −.25; P < .0001). Lower delayed admission NLR was also associated with GFOs (SMD = −.80; 95%CI = −.91 to −.68; P < .0001). Higher admission NLR was significantly associated with mortality (SMD = .49; 95%CI = .12 to .85; P = .009), intracerebral haemorrhage (ICH) (SMD = .34; 95% CI = .09 to .59; P = .007), symptomatic ICH (sICH) (SMD = .48; 95% CI = .07 to .90; P = .022) and stroke-associated infection or pneumonia (SMD = .85; 95% CI = .50, 1.19; P < .0001). Higher delayed NLR was significantly associated with sICH (SMD = 1.40; 95% CI = .60 to 2.19; P = .001), ICH (SMD = .94; 95% CI = .41 to 1.46; P < .0001) and mortality (SMD = 1.12; 95% CI = .57 to 1.67; P < .0001). There were variations in outcomes across RT groups.ConclusionHigher admission or delayed NLR is significantly associated with worse morbidity, mortality and safety outcomes in AIS patients receiving RT.

Rho-Kinase inhibition decreases focal cerebral ischemia-induced glial activation in rats.

BackgroundRho-kinase inhibition in a rat middle cerebral artery occlusion (MCAO) model is reported to improve neurological functions and decrease infarction size.ObjectiveThe objective of this study is to investigate the underlying mechanisms of such improvement by evaluating the effects of Rho-kinase inhibition on astrocytes and microglial accumulation and activation in this condition.MethodsAdult male Sprague-Dawley (SD) rats were used to generate the MCAO model, which received an I.P injection of a chemical Rho-kinase inhibitor (Fasudil- 5 mg/kg/day) or vehicle (PBS) for 2 and 4 days.ResultsFasudil treatment significantly decreased the stroke volumes and water content in the lesion areas, as revealed by MRI. Immunostaining and Western blotting results demonstrated that Fasudil significantly decreased the levels of Aquaporin-4, a water channel protein. The number of GFAP+ astrocytes and Iba-1+ macrophage/microglia was decreased in the lesion areas. Proinflammatory transcription factor NF-κB protein levels were decreased in the Fasudil group 2 days after MCAO. Also, proinflammatory mediators including TNF-α, IL-1β, and iNOS levels were decreased. In vitro migration study using a human microglial cell line (HMO6) confirmed the inhibitory effects of Fasudil on the process. Fasudil also decreased combined IL-1β and IFNγ-induced NF-κB nuclear translocation in HMO6. Moreover, Fasudil transiently decreased combined IL-1β and IFNγ-induced iNOS, TNFα, and IL-1β mRNA levels in HMO6.ConclusionOur study demonstrates the inhibitory effects of Rho-kinase on NF-κB-mediated glial activation and cerebral edema, which might be a promising therapeutic target in acute cerebral ischemia conditions.