Ischemic Cascade Research Articles

Agmatine: An Emerging Approach for Neuroprotection in Recurrent Ischemic Stroke Events in a Murine Model.

This study investigates the effect of agmatine on reducing mortality, neurobehavioral alterations, infarct size, and expression of pro-inflammatory cytokines in mice subjected to bilateral carotid thrombosis. Under pentobarbital anesthesia, the left common carotid artery was exposed to 6% FeCl3. Thirty-two days later, the same procedure was performed on the right common carotid artery. Subsequently, Agmatine (100 mg/kg) was administered 15 min after the second procedure, and in another experimental group, the dose of Agmatine was repeated at 72 h. Administration of agmatine extended survival in ischemic animals up to 72 h for the single-dose group and up to 96 h for the repeated-dose group, without significant increases in neurological deficits or infarct area size. This neurobehavioral effect was also observed in sham animals treated with agmatine. In ischemic animals, agmatine administration improved digging behavior and reduced recovery times, consistently shorter in those animals treated with repeated doses. RT-PCR analyses revealed a positive regulation of the cytokine IL-1β in agmatine-treated animals, which has been associated with recovery stages. The results suggest that the observed effect may be attributed to the multiple interactions of agmatine with ischemic cascade events, highlighting its anti-inflammatory role.

Phosphatidylserine: A Novel Target for Ischemic Stroke Treatment.

Over the past 40 years, research has heavily emphasized stroke treatments that directly target ischemic cascades after stroke onset. Much attention has focused on studying neuroprotective drugs targeting one aspect of the ischemic cascade. However, the single-target therapeutic approach resulted in minimal clinical benefit and poor outcomes in patients. Considering the ischemic cascade is a multifaceted and complex pathophysiological process with many interrelated pathways, the spotlight is now shifting towards the development of neuroprotective drugs that affect multiple aspects of the ischemic cascade. Phosphatidylserine (PS), known as the "eat-me" signal, is a promising candidate. PS is involved in many pathophysiological changes in the central nervous system after stroke onset, including apoptosis, inflammation, coagulation, and neuronal regeneration. Moreover, PS might also exert various roles in different phases after stroke onset. In this review, we describe the synthesis, regulation, and function of PS under physiological conditions. Furthermore, we also summarize the different roles of PS after stroke onset. More importantly, we also discuss several treatment strategies that target PS. We aim to advocate a novel stroke care strategy by targeting PS through a translational perspective.

The deletion of AQP4 and TRPV4 affects astrocyte swelling/volume recovery in response to ischemia-mimicking pathologies.

Astrocytic Transient receptor potential vanilloid 4 (TRPV4) channels, together with Aquaporin 4 (AQP4), are suspected to be the key players in cellular volume regulation, and therefore may affect the development and severity of cerebral edema during ischemia. In this study, we examined astrocytic swelling/volume recovery in mice with TRPV4 and/or AQP4 deletion in response to in vitro ischemic conditions, to determine how the deletion of these channels can affect the development of cerebral edema. We used three models of ischemia-related pathological conditions: hypoosmotic stress, hyperkalemia, and oxygenglucose deprivation (OGD), and observed their effect on astrocyte volume changes in acute brain slices of Aqp4-/-, Trpv4-/- and double knockouts. In addition, we employed single-cell RT-qPCR to assess the effect of TRPV4 and AQP4 deletion on the expression of other ion channels and transporters involved in the homeostatic functioning of astrocytes. Quantification of astrocyte volume changes during OGD revealed that the deletion of AQP4 reduces astrocyte swelling, while simultaneous deletion of both AQP4 and TRPV4 leads to a disruption of astrocyte volume recovery during the subsequent washout. Of note, astrocyte exposure to hypoosmotic stress or hyperkalemia revealed no differences in astrocyte swelling in the absence of AQP4, TRPV4, or both channels. Moreover, under ischemia-mimicking conditions, we identified two distinct subpopulations of astrocytes with low and high volumetric responses (LRA and HRA), and their analyses revealed that mainly HRA are affected by the deletion of AQP4, TRPV4, or both channels. Furthermore, gene expression analysis revealed reduced expression of the ion transporters KCC1 and ClC2 as well as the receptors GABAB and NMDA in Trpv4-/- mice. The deletion of AQP4 instead caused reduced expression of the serine/cysteine peptidase inhibitor Serpina3n. Thus, we showed that in AQP4 or TRPV4 knockouts, not only the specific function of these channels is affected, but also the expression of other proteins, which may modulate the ischemic cascade and thus influence the final impact of ischemia.

Combined low-dose dobutamine and exercise stress echocardiography: a new hybrid protocol to detect inducible ischaemia.

Myocardial response to stress echocardiography may be elicited physiologically, through exercise, or pharmacologically, often with dobutamine. Both have advantages but also limitations due to reduced exercise capacity or side-effects to stressor agent/lack of closeness to true pathophysiology of ischaemic cascade. We have combined low-dose dobutamine and exercise, creating a 'hybrid' protocol to utilize the advantages of both techniques and limit the drawbacks. The aim of the study was to evaluate its safety and feasibility. In the hybrid protocol, low-dose dobutamine infusion (up to 10 µg/kg/min) is enhanced by supine bicycle exercise at 3-min increments of workload of 25 W to achieve target heart rate (THR). We analysed safety and outcome data for all the patients who underwent this protocol from 2017 to 2022. Out of 835, 727 (87.1%) patients referred for evaluation of ischaemia underwent the hybrid protocol. The median age was 61 years old and 61% (442/727) were men. The median exercise time was 11 (9-13.5) min with a median maximum workload of 100 W (75-125). Out of 727, 670 (92.2%) achieved THR. Atropine was not used. Out of 727, 192 (26.4%) of studies were positive for ischaemia. Out of 122, 102 (83.6%) with positive stress who underwent invasive angiography had significant coronary disease. The incidence of complications was low: 1/727-severe arrhythmia, 5/727 (0.7%) developed a vasovagal episode, and 14/727 (1.9%) had a hypertensive response to exercise. Our findings suggest that this protocol is safe, feasible, and has a high success rate in achieving THR.

Mobilizing endogenous neuroprotection: the mechanism of the protective effect of acupuncture on the brain after stroke.

Given its high morbidity, disability, and mortality rates, ischemic stroke (IS) is a severe disease posing a substantial public health threat. Although early thrombolytic therapy is effective in IS treatment, the limited time frame for its administration presents a formidable challenge. Upon occurrence, IS triggers an ischemic cascade response, inducing the brain to generate endogenous protective mechanisms against excitotoxicity and inflammation, among other pathological processes. Stroke patients often experience limited recovery stages. As a result, activating their innate self-protective capacity [endogenous brain protection (EBP)] is essential for neurological function recovery. Acupuncture has exhibited clinical efficacy in cerebral ischemic stroke (CIS) treatment by promoting the human body's self-preservation and "Zheng Qi" (a term in traditional Chinese medicine (TCM) describing positive capabilities such as self-immunity, self-recovery, and disease prevention). According to research, acupuncture can modulate astrocyte activity, decrease oxidative stress (OS), and protect neurons by inhibiting excitotoxicity, inflammation, and apoptosis via activating endogenous protective mechanisms within the brain. Furthermore, acupuncture was found to modulate microglia transformation, thereby reducing inflammation and autoimmune responses, as well as promoting blood flow restoration by regulating the vasculature or the blood-brain barrier (BBB). However, the precise mechanism underlying these processes remains unclear. Consequently, this review aims to shed light on the potential acupuncture-induced endogenous neuroprotective mechanisms by critically examining experimental evidence on the preventive and therapeutic effects exerted by acupuncture on CIS. This review offers a theoretical foundation for acupuncture-based stroke treatment.

Pathogenetic scenarios of the development of brain ischemia and the main elements of the ischemic cascade

Ischemic stroke is one of the leading causes of disability and mortality. The key approaches to the treatment of this pathology are thrombolytic therapy and thromboaspiration. Despite their proven efficacy, the application of these methods is limited by a relatively narrow therapeutic window. There remains a great relevance in the further study of the molecular mechanisms of ischemic- reperfusion brain damage within the framework of the ischemic cascade concept. The impact on the mechanisms of induction and implementation of various types of programmed cell death with the help of pharmacological agents is a promising approach to reduce brain damage in ischemic stroke. This review considers the key processes leading to irreversible damage to neurons and their death. The mechanisms of formation and the role of excitotoxicity, calcium overload, oxidative and nitrosyl stress, mitochondrial dysfunction, as well as the triggering of signaling pathways of apoptosis and aseptic inflammation are considered in detail. The issue of various variants of cell death against the background of these pathological processes is discussed. Along with the consideration of signaling pathways that contribute to the progression of brain damage, special attention is paid to the activation of protective signaling mechanisms during ischemia, which provide an increase in cell resistance to death.

Pharmacological neuroprotection in cerebrovascular insufficiency: Possible approaches

This review analyzed the literature data and results of our research on the experimental and clinical studies of the possibilities of pharmacological neuroprotection in ischemic brain lesions. Neuroprotection is one of the strategic directions of specific pharmacotherapy for cerebrovascular insufficiency. Different approaches to pharmacological neuroprotection are possible, considering the main pathogenetic pathways of the ischemic cascade and physiological mechanisms of neuroprotection. Pharmacological neuroprotection can be achieved by blocking the pathogenetic links of the ischemic cascade (primarily glutamate excitotoxicity and oxidant stress) and inducing physiological processes associated with neuroplasticity and neurotrophy. The issues related to the use of various pharmacotherapeutic groups for primary and secondary neuroprotection are discussed. The optimal choice of pathogenetic and physiological targets for primary and secondary pharmacological neuroprotection is an important component in the development of pharmacotherapy strategies for ischemic brain lesions because it consistently increases the resistance of brain cells to ischemia/hypoxia and stimulates reparative recovery processes in the central nervous system. Rationally selected pathways and drugs for pharmacological neuroprotection determine their effectiveness in ischemic brain lesions.

Inhibition of Anaplastic Lymphoma Kinase Protects From Ischemic Stroke.

Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke. Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined. We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15. Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke.

Hemorrhagic transformation of cerebral infarction: risk factors, diagnosis, and new approaches to treatment

Background. Hemorrhagic transformation (HT) is a frequent complication of acute cerebral infarction, which is unfavo­rable for the treatment and prognosis of patients. It can be divided into two main subtypes, hemorrhagic infarction, and parenchymal hematoma, depending on the type of hemorrhage. Although the pathophysiological mechanism of HT is still unclear, hypotheses have been proposed about the loss of microvascular integrity and impaired neurovascular homeostasis. The purpose of the study was to analyze the current scientific literature on risk factors, diagnosis, and new approaches to the treatment of hemorrhagic transformation of cerebral infarction. Materials and methods. A literature search using keywords was conducted in Web of Science, Scopus, PubMed, and Elsevier databases. Results. Ischemic tissues have a natural tendency to bleed. In addition, the first trials of recanalization using intravenous thrombolysis showed an increase in the incidence of mild to severe intracranial hemorrhages. Symptomatic intracerebral hemorrhage is closely associated with poor outcomes and is an important factor in recanalization decisions. The development of HT after stroke involves numerous interrelated pathological processes from peripheral blood cells to neurovascular units such as hyperactive ischemic cascades with increased levels of matrix metalloproteinases, excessive reactive oxygen species, coagulopathy, blood-brain barrier breakdown, and reperfusion injury. A number of risk factors or prognostic factors for HT after cerebral infarction have been identified, namely the use of antiplatelet agents or anticoagulants, infarct size, atrial fibrillation, hypertension, age, gender, heart failure, coronary artery disease, diabetes mellitus, lipid profile, reperfusion therapy, and white matter hyperintensity load. The incidence of HT is reported mainly in clinical studies using brain imaging techniques such as computed tomography or magnetic resonance imaging, diffusion weighted imaging, and perfusion weighted imaging. Recombinant tissue plasminogen activator therapy and mechanical thrombectomy are currently the main treatments for ischemic stroke, but reperfusion injury due to revascula­rization increases the risk of cerebral hemorrhage. Understanding the risk factors and in-depth evaluation of predictors can significantly help physicians develop strategies to reduce the occurrence of HT, as well as provide insight into the pathophysiological mechanism of the disease. Conclusions. Patients at risk of hemorrhagic transformation require invasive and non-invasive neuromonitoring to help make decisions in decompressive neurosurgery for large cerebellar infarction, specific cardiorespiratory treatment, nutrition, blood pressure control, biochemical parameters, and the choice of an individual management strategy.

Inhibition of leukocyte migration after ischemic stroke by VE-cadherin mutation in a mouse model leads to reduced infarct volumes and improved motor skills.

To distinguish between the genuine cellular impact of the ischemic cascade by leukocytes and unspecific effects of edema and humoral components, two knock-in mouse lines were utilized. Mouse lines Y731F and Y685F possess point mutations in VE-cadherin, which lead to a selective inhibition of transendothelial leukocyte migration or impaired vascular permeability. Ischemic stroke was induced by a model of middle cerebral artery occlusion. Analysis contained structural outcomes (infarct volume and extent of brain edema), functional outcomes (survival analysis, rotarod test, and neuroscore), and the extent and spatial distribution of leukocyte migration (heatmaps and fluorescence-activated cell sorting (FACS) analysis). Inhibition of transendothelial leukocyte migration as in Y731F mice leads to smaller infarct volumes (52.33±4719 vs. 70.43±6483mm3 , p=.0252) and improved motor skills (rotarod test: 85.52±13.24s vs. 43.06±15.32s, p=.0285). An impaired vascular permeability as in Y685F mice showed no effect on structural or functional outcomes. Both VE-cadherin mutations did not influence the total immune cell count or spatial distribution in ischemic brain parenchyma. Selective inhibition of transendothelial leukocyte migration by VE-cadherin mutation after ischemic stroke in a mouse model leads to smaller infarct volumes and improved motor skills.

Strain imaging as an early predictor in acute myocardial infarction – An augmented cross-sectional study

IntroductionCardiac fibres are affected invariably in myocardial infarction, with longitudinal strain being the earliest to be detected in the ischaemic cascade. The present study aims to assess strain imaging in acute myocardial infarction (AMI) patients admitted to the cardiology department at our institute and correlate GLS and DESL findings with other markers for myocardial function. Methods and materialThis augmented cross-sectional study was conducted amongst the patients admitted with diagnosis of AMI. During the study period, 157 subjects were sampled through convenience sampling, and examined as well as tested with routine investigations at baseline. The subjects were then followed through at first, third and six months, and findings noted. Chi-square was used to assess the crude association between sample characteristics. Pearson correlation and student t-test were used to find association between continuous variables. ResultsAfter screening 564 patients, 157 patients were included in the study after fulfilment of inclusion and exclusion criteria. A significant difference was found in baseline GLS scores and NTproBNP levels at 6 months in alive patients with STEMI, t (21.728) = −5.717, p < .001. Out of the 50 NSTEMI patients, 35 (70 %) were positive for ESL, similarly out of 43 STEMI patients without any RWMA, ESL was positive in 39 (90.02 %) patients. ConclusionsGLS by STE has good correlation with LVEF, WMSI and NT pro-BNP and it is an independent predictor of mortality and heart failure among patients with AMI.

Traditional Chinese medicines treat ischemic stroke and their main bioactive constituents and mechanisms.

Ischemic stroke (IS) remains one of the leading causes of death and disability in humans. Unfortunately, none of the treatments effectively provide functional benefits to patients with IS, although many do so by targeting different aspects of the ischemic cascade response. The advantages of traditional Chinese medicine (TCM) in preventing and treating IS are obvious in terms of early treatment and global coordination. The efficacy of TCM and its bioactive constituents has been scientifically proven over the past decades. Based on clinical trials, this article provides a review of commonly used TCM patent medicines and herbal decoctions indicated for IS. In addition, this paper also reviews the mechanisms of bioactive constituents in TCM for the treatment of IS in recent years, both domestically and internationally. A comprehensive review of preclinical and clinical studies will hopefully provide new ideas to address the threat of IS.

INOS expression in the pyramid layer of the rat hippocampus in the modeling of chronic cerebral discirculatory disorder

AbstractBackgroundStudying of various forms of NO‐synthases is of great interest, since they are involved in many of the mechanisms of neuronal injury, aggravating the ischemic cascade and negatively affect the clinical status of cerebrovascular diseases. Impaired functioning of NO synthase plays an important role in the progressing of neurodegenerative diseases, since nitric oxide is a modulator of neuroplasticity.MethodChronic cerebrovascular disorder was modeled on rats by the method of overloading in the caudo‐cranial vector with a force 9 G for 5 minutes with an interval of 12 hours for 28 days. The level of iNOS expression was assessed by calculating the relative area of the immunoreactive material.ResultThe heterogeneity of the distribution of the immunoreactive material was expressed both in dust‐like cytoplasmic accumulation and in the presence of small‐lumpy deposits of iNOS‐positive material in the neurons of the pyramidal layer and in the neuropil, and in glial cells the intensity of expression was more pronounced, reaching a pronounced one. The relative area of iNOS‐positive material increased most significantly in CA3, by 8.3% (p&lt;0.001), amounting to 12.1% [9.8;14.3]%. In CA1, the increase in the same indicator relative to the control was 3.9% (p&lt;0.001), reaching 5.7 [4.5;6.1]%. In CA2 and CA4, respectively, the increase in the relative area of the IRM was 4.5% (p&lt;0.05).ConclusionWe presume that the pronounced neuronal injury that is observed in the chronic cerebrovascular disorder modeling is a factor in the disruption of the hematoencephalic barrier, leading to edema, the subsequent acquisition of a pro‐inflammatory phenotype by astrocytic and microglia and the switch from the constitutive type of NO‐synthesis to the predominantly inducible type associated with activation of iNOS.

Image Classification of Stroke Blood Clot Origin Using Deep Convolutional Neural Networks and Visual Transformers: A Kaggle Competition

Stroke is one of two main causes of death worldwide. Many individuals suffer from ischemic stroke every year. Only in US, more over 700,000 individuals meet ischemic stroke due to blood clot blocking an artery to the brain every year. «Stroke symptoms typically start suddenly, over seconds to minutes, and in most cases do not progress further. The symptoms depend on the area of the brain affected. The more extensive the area of the brain affected, the more functions that are likely to be lost. » «Ischemic stroke occurs because of a loss of blood supply to part of the brain, initiating the ischemic cascade. » In the case of subsequent strokes, it is possible to mitigate consequences if physicians can determine stroke etiology. The paper describes particular approach how to apply Artificial Intelligence for purposes of separating two major acute ischemic stroke (AIS) etiology subtypes: cardiac and large artery atherosclerosis. Four deep neural network architectures and simple ensemble method are used in the approach.

Acute inhibition of acid sensing ion channel 1a after spinal cord injury selectively affects excitatory synaptic transmission, but not intrinsic membrane properties, in deep dorsal horn interneurons.

Following a spinal cord injury (SCI), secondary damage mechanisms are triggered that cause inflammation and cell death. A key component of this secondary damage is a reduction in local blood flow that initiates a well-characterised ischemic cascade. Downstream hypoxia and acidosis activate acid sensing ion channel 1a (ASIC1a) to trigger cell death. We recently showed that administration of a potent venom-derived inhibitor of ASIC1a, Hi1a, leads to tissue sparing and improved functional recovery when delivered up to 8 h after ischemic stroke. Here, we use whole-cell patch-clamp electrophysiology in a spinal cord slice preparation to assess the effect of acute ASIC1a inhibition, via a single dose of Hi1a, on intrinsic membrane properties and excitatory synaptic transmission long-term after a spinal cord hemisection injury. We focus on a population of interneurons (INs) in the deep dorsal horn (DDH) that play a key role in relaying sensory information to downstream motoneurons. DDH INs in mice treated with Hi1a 1 h after a spinal cord hemisection showed no change in active or passive intrinsic membrane properties measured 4 weeks after SCI. DDH INs, however, exhibit significant changes in the kinetics of spontaneous excitatory postsynaptic currents after a single dose of Hi1a, when compared to naive animals (unlike SCI mice). Our data suggest that acute ASIC1a inhibition exerts selective effects on excitatory synaptic transmission in DDH INs after SCI via specific ligand-gated receptor channels, and has no effect on other voltage-activated channels long-term after SCI.

Use of biomarkers for predicting a malignant course in acute ischemic stroke: an observational case–control study

Acute ischemic stroke is a sudden neurological event caused by brain ischemia. Patients with large vessel occlusion are at high risk of developing significant cerebral edema, which can lead to rapid neurological decline. The optimal timing for decompressive hemicraniectomy to prevent further brain damage is still uncertain. This study aimed to identify potential predictors of severe brain edema. The data indicate that specific cytokines may help identify patients with a higher risk of developing life-threatening brain swelling in the early phase post-stroke. The association between a positive biomarker and the outcome was calculated, and three biomarkers—S100B protein, MMP-9, and IL-10—were found to be significantly associated with malignant edema. A model was derived for early predicting malignant cerebral edema, including S100B protein and IL-1 beta. These findings suggest that molecular biomarkers related to the ischemic cascade may be a helpful way of predicting the development of malignant cerebral edema in ischemic stroke patients, potentially widening the time window for intervention and assisting in decision-making. In conclusion, this study provides insights into the molecular mechanisms of severe brain edema and highlights the potential use of biomarkers in predicting the course of ischemic stroke.

Integrated inflammatory signaling landscape response after delivering Elovanoid free-fatty-acid precursors leading to experimental stroke neuroprotection

Despite efforts to identify modulatory neuroprotective mechanisms of damaging ischemic stroke cascade signaling, a void remains on an effective potential therapeutic. The present study defines neuroprotection by very long-chain polyunsaturated fatty acid (VLC-PUFA) Elovanoid (ELV) precursors C-32:6 and C-34:6 delivered intranasally following experimental ischemic stroke. We demonstrate that these precursors improved neurological deficit, decreased T2WI lesion volume, and increased SMI-71 positive blood vessels and NeuN positive neurons, indicating blood–brain barrier (BBB) protection and neurogenesis modulated by the free fatty acids (FFAs) C-32:6 and C-34:6. Gene expression revealed increased anti-inflammatory and pro-homeostatic genes and decreases in expression of pro-inflammatory genes in the subcortex. Additionally, the FFAs elicit a comprehensive downregulation of inflammatory microglia/monocyte-derived macrophages and astrocyte-associated genes in the subcortical region. Functional analysis reveals inhibition of immune-related pathways and production of upstream molecules related to detrimental signaling events in post-stroke acute and subacute phases.

Comparative influence of mesenchymal stromal cells of different origin on DNA fragmentation of neuronal nuclei during ischemia-reperfusion of the somatosensory cortex of the rat brain

Relevance: One of the main causes of stroke in acute cerebrovascular accident (ACVA) is ischemia, which begins with the formation of an acute neuronal energy deficit with subsequent activation of the "ischemic cascade" reactions that lead to irreversible damage to nervous tissue. Aim: To compare the effect of mesenchymal stromal cells (MSCs) of different origin and human MSCs from Wharton's jelly lysate on neuroapoptotic changes in the somatosensory cortex of the rat brain in conditions of model ischemia-reperfusion (IR) performed by ductal cytoflowmetry. Materials and methods: The experiment was carried out using 165 four-month-old male Wistar rats weighing 160-190 g, which were subjected to bilateral 20-minute transient ischemia-reperfusion (IR) of the internal carotid arteries. After modeling the pathology, the animals were injected into the femoral vein (iv) with MSCs obtained from umbilical cord Wharton jelly, human and rat adipose tissue in the amount of 106 cells/animal. Other groups of experimental animals were intravenously injected with fetal rat fibroblasts in the amount of 106 cells/animal (in 0.2 ml of physiological solution) and MSCs from umbilical cord Wharton's jelly lysate in a dose of 0.2 ml/animal. Control animals were injected intravenously with 0.2 ml of physiological solution. The level of DNA fragmentation in the nuclei of neurons of the somatosensory cortex of rats on the 7th day after ischemia-reperfusion was studied by flow cytometry. The research was carried out on a flow cytometer "Partech РАС" of the company Partech, Germany. The statistical significance of the differences was assessed by Student's t-test. Results: The study noted an increase in the level of fragmented DNA in a group of animals with IR by 3.25 times 7 days after model IR. The performed treatment showed that in groups with transplanted MSCs of various origins and MSC lysate from human Wharton's jelly cells, the intensity of DNA fragmentation in the nuclei of neurons in rat brain somatosensory cortex reliably decreased in1.8-2. 6 times compared with the group of control pathology (IR without treatment). Conclusions: Experimental 20-minute IR of the brain of rats forms a persistent focus of necrotic and apoptotic death of neurons, which is manifested by an increase in fragmented DNA (3.25 times). Intravenous transplantation of MSCs of various origin and lysate of MSCs from human Wharton jelly has a therapeutic effect in model IR, which is manifested by a decrease in the processes of neuro-destruction and neuroapoptosis in the area of ischemic brain damage Such effect is a link to the polytrophic mechanism of MSCs neuro-protective action.

Oxidative stress and early mortality in acute ischemic stroke: A prospective cohort study

ABSTRACT Background Malondialdehyde (MDA) is an oxidative stress biomarker, which represents a unifying mechanism of brain injury that occurs throughout the ischemic stroke cascade. The current study aimed to examine whether or not acute ischemic stroke (AIS) patients who had elevated serum MDA levels at admission had an increased risk of mortality and a worse functional outcome three months later. Methods An observational, prospective cohort study that enrolled 90 patients with AIS. The patients were examined in the first 24 hours and then followed up for three months to assess mortality, short-term neurological functional outcome, and neurological disability by the Modified Rankin Scale (MRS). Results The mean of serum MDA level among AIS patients was 6.3 ± 3.7 nmol/ml. Non-survivor cases were associated with statistically significantly higher serum MDA levels compared to survivors (9.7 ± 4.3 vs. 5.3 ± 2.8, p < 0.001), respectively. Patients with severe stroke, according to NIHSS score, were associated with significantly (p < 0.05) higher MDA levels compared to moderate and mild cases (7.4 ± 4.3 vs. 5.4 ± 2.6 vs. 3.3 ± .6). At a cutoff point of ≥ 6.7 nmol/ml, the area under the curve (AUC) for serum MDA levels as a predictor of mortality was 0.8 (0.69–0.91; p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value were 77%, 80%, 89.5%, and 48.5%, respectively. Multivariate regression demonstrated that MDA level was a significant independent predictor of mortality among patients with AIS (OR = 1.29, 95% CI: 1.01 to 1.65; p = 0.041). Conclusion MDA serum level was significantly higher in non-survivors than in survivors patients, so MDA could be used as a predictor for early mortality and short-term outcome of cases with AIS.

Gut Dysbiosis: A New Avenue for Stroke Prevention and Therapeutics.

A stroke is a serious life-threatening condition and a leading cause of death and disability that happens when the blood vessels to part of the brain are blocked or burst. While major advances in the understanding of the ischemic cascade in stroke was made over several decades, limited therapeutic options and high mortality and disability have caused researchers to extend the focus toward peripheral changes beyond brain. The largest proportion of microbes in human body reside in the gut and the interaction between host and microbiota in health and disease is well known. Our study aimed to explore the gut microbiota in patients with stroke with comparison to control group. Fecal samples were obtained from 51 subjects: 25 stroke patients (18 hemorrhagic, 7 ischemic) and 26 healthy control subjects. The variable region V3-V4 of the 16S rRNA gene was sequenced using the Illumina MiSeq platform. PICRUSt2 was used for prediction of metagenomics functions. Our results show taxonomic dysbiosis in stroke patients in parallel with functional dysbiosis. Here, we show that stroke patients have (1) increased Parabacteroides and Escherichia_Shigella, but decreased Prevotella and Fecalibacterium; (2) higher transposase and peptide/nickel transport system substrate-binding protein, but lower RNA polymerase sigma-70 factor and methyl-accepting chemotaxis protein, which are suggestive of malnutrition. Nutrients are essential regulators of both host and microbial physiology and function as key coordinators of host-microbe interactions. Manipulation of nutrition is expected to alleviate gut dysbiosis and prognosis and improve disability and mortality in the management of stroke.