Cerebral Ischemic Stroke Research Articles

Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial.

Sovateltide (Tycamzzi™), an endothelin-B (ET-B) receptor agonist, increases cerebral blood flow, has anti-apoptotic activity, and promotes neural repair following cerebral ischaemic stroke. The objectives of this study were to evaluate the efficacy and safety of sovateltide in adult participants with acute cerebral ischaemic stroke. This was a randomised, double-blind, placebo-controlled, multicentre, Phase III clinical trial of sovateltide in participants with cerebral ischaemic stroke receiving standard of care (SOC) in India. Patients aged 18-78 years presenting up to 24 h after the onset of symptoms with radiologic confirmation of ischaemic stroke and a National Institutes of Health Stroke Scale score (NIHSS) of ≥ 6were enrolled. Patients with recurrent stroke, receiving endovascular therapy, or with intracranial haemorrhage were excluded. The study drug (saline or sovateltide [0.3 µg/kg] was administered intravenously in three doses at 3 ± 1 h intervals on Days 1, 3, and 6, and follow-up was 90 days). The Multivariate Imputation by Chained Equations (MICE) was used to impute the missing assessments on the endpoints. An unpaired t-test, two-way analysis of variance with Tukey's multiple comparison test, and the Chi-square test were used for the statistical analysis. The objective was to determine at Day 90 (1) the number of patients with a modified Rankin Scale score (mRS) 0-2, and (2) the number of patients with an NIHSS 0-5 at 90 days. Patients were randomised with 80 patients in the sovateltide and 78 in the control group. Patients received the investigational drug at about 18 h of stroke onset in both control and sovateltide groups. The median NIHSS at randomisation was 10.00 (95% CI 9.99-11.65) in the control group and 9.00 (95% CI 9.11-10.46) in the sovateltide group. Seventy patients completed the 90-day follow-up in the control group and 67 in the sovateltide group. The proportion of intention-to-treat (ITT) patients with mRS 0-2 score at Day 90 post-randomisation was 22.67% higher (odds ratio [OR] 2.75, 95% CI 1.37-5.57); similarly, the proportion of patients with NIHSS score of 0-5 at Day 90 was 17.05% more (OR 2.67, 95% CI 1.27-5.90) in the sovateltide group than in the control group. An improvement of ≥ 2 points on the mRS was observed in 51.28% and 72.50% of patients in the control and sovateltide groups, respectively (OR 2.50, 95% CI 1.29-4.81). Seven of 78 patients (8.97%) in the control group and 7 of 80 (8.75%) in the sovateltide group developed intracranial haemorrhage (ICH). The adverse events were not related to sovateltide. The sovateltide group had a greater number of cerebral ischaemic stroke patients with lower mRS and NIHSS scores at 90 days post-treatment than the control group. This trial supported the regulatory approval of sovateltide in India, but a multinational RESPECT-ETB trial will be conducted for US approval. Clinical Trials Registry, India (CTRI/2019/09/021373) and the United States National Library of Medicine, ClinicalTrials.gov (NCT04047563).

Research Progress on the Pharmacological Mechanism of Traditional Chinese Medicine Danshen in the Treatment of Cerebral Ischemic Stroke

Cerebral ischemic stroke (CIS) is an acute cerebrovascular disease characterized by focal neurological deficits. Many modern scholars believe that the pathogenesis of CIS is related to factors such as endothelial injury, oxidative stress imbalance, neuroinflammation, cell apoptosis and autophagy, calcium overload, and excessive accumulation of oxygen free radicals. Traditional Chinese medicine believes that the pathogenesis of CIS is obstructed meridians, phlegm and blood stasis, and obstruction of the brain and orifices. Danshen, as a commonly used traditional Chinese medicine in clinical practice, has the effects of promoting blood circulation and removing blood stasis, unblocking meridians and relieving pain, clearing the heart and eliminating restlessness, cooling blood and eliminating carbuncle. In addition, modern pharmacological research has found that the specific pharmacological components of Salvia miltiorrhiza include tanshinone, salvianolic acid, shikimic acid, danshensu, protocatechualdehyde, etc. It has antioxidant stress, regulation of cell autophagy, anti-inflammatory factors, antiplatelet aggregation, and protection of vascular endothelium. This article aims to analyze and summarize the pharmacological mechanism of salvia miltiorrhiza in treating CIS, providing scientific basis for clinical application of salvia miltiorrhiza in treating CIS.

Outcome and life expectancy associated with novel subgroups of atrial fibrillation: a data-driven cluster analysis

Abstract Background/Introduction Atrial fibrillation (AF) presents a significant global health burden, affecting millions and associated with elevated risks of mortality, heart failure, and stroke despite current treatment strategies. The current diagnosis of AF relies on episode characteristics, yet its heterogeneity calls for personalized assessment incorporating clinical features, biomarkers, and substrate determination for improved classification and management. Purpose This study aimed to develop a refined classification of AF according to comprehensive risk factors to identify patients at high-risk for poor prognosis and their life expectancy, aiming to facilitate personalized interventions. Methods A total of 7,391 participants aged 40-69 with AF at baseline, from UK Biobank, were recruited in the main analyses. Firstly, LASSO regression with Cox model and factor analysis were adopted for identification and integration of principal risk factors. Second, Consensus clustering analysis was employed to estimate the optimal cluster number and group all 7,391 participants. Difference in the risk of death and major complications, as well as reductions in life expectancy, among clusters were estimated. Replication was done in 2,399 participants with newly diagnosed AF within two years after baseline. Results Risk factors for AF were categorized into seven aspects (metabolic factors, respiratory factors, cardiovascular factors, renal and immunity diseases, mental health, acute illness, age), based on the correlation between them. Five distinct AF clusters were identified according to these seven characteristics: acute illness-related (Cluster 1), mental health-related (Cluster 2), cardiovascular disease-related (Cluster 3), immune-and-renal disease-related (Cluster 4), and respiratory-and-metabolism disease-related AF (Cluster 5). Patients with respiratory-and-metabolism disease-related AF had the highest risk of death, acute myocardial infarction, heart failure, and cerebral ischemic stroke, while those with acute illness-related AF had the lowest corresponding risk. In addition, compared with individuals with acute illness-related AF, those with respiratory-and-metabolism disease-related and mental health-related AF had the top 2 greatest loss of life expectancy. Furthermore, genetic variants for AF had different effect among the five clusters. Replication analysis confirmed the result stability. Conclusion A novel AF classification was developed, which provided insights into varying life expectancy and risks of death and complications among AF subgroups with distinct characteristics. It offers a practical approach for identifying high-risk patients, which may help to tailor precise interventions for AF management.Graphic abstractCluster features

METTL14 Promotes Ischemic Stroke-induced Brain Injury by Stabilizing HDAC3 Expression in an m6A-IGF2BP3 Mechanism.

N6-methyladenosine (m6A) modification is the most abundant post-transcriptional modification of mRNAs and has been identified to play critical roles in ischemic stroke (IS). Herein, this study aimed to investigate the function and mechanism of Methyltransferase-like 14 (METTL14) methylase in cerebral IS. Murine BV-2 microglial cell OGD/R models and rat middle cerebral artery occlusion (MCAO) models were established to mimic IS-induced neuronal damage in vitro and brain injury in vivo. Levels of METTL14, Histone Deacetylase 3 (HDAC3) and cGAS-STING axis-related proteins were detected using qRT-PCR or western blotting. Cell proliferation and inflammation were assessed by CCK-8 assay, EdU assay and ELISA. Flow cytometry detected microglia polarization. Cell pyroptosis was analyzed by detecting related-protein markers by western blotting. The m6A modification was determined by methylated RNA immunoprecipitation assay. Brain injury was analyzed by evaluating infarct volume and neurologic score. METTL14 levels were higher in OGD/R-induced microglial cells, primary microglia and infarct brain tissues of rat MCAO models. Functionally, METTL14 silencing reversed OGD/R-induced proliferation inhibition, inflammation and pyroptosis in microglial cells and primary microglia in vitro, and ameliorated cerebral ischemic injury in rat MCAO models. Mechanistically, METTL14 induced HDAC3 m6A modification in an IGF2BP3-dependent manner, and could activate cGAS-STING pathway through HDAC3. Moreover, HDAC3 overexpression reversed the neuroprotective effects of METTL14 silencing. METTL14 silencing reversed ischemic stroke-induced brain injury by inducing HDAC3 m6A modification in an IGF2BP3-dependent mechanism, recommending a novel insight for ameliorating cerebral ischemic stroke.

Ischemia-induced endogenous Nrf2/HO-1 axis activation modulates microglial polarization and restrains ischemic brain injury.

Cerebral ischemic stroke accounts for more than 80% of all stroke cases. During cerebral ischemia, reactive oxygen species produced in the ischemic brain induce oxidative stress and inflammatory responses. Nrf2 is a transcription factor responsible for regulating cellular redox balance through the induction of protective antioxidant and phase II detoxification responses. Although the induction of endogenous Nrf2/HO-1 axis activation has been observed in the ischemic brain, whether ischemia-induced endogenous Nrf2/HO-1 axis activation plays a role in modulating microglia (MG) phenotypes and restraining ischemic brain injury is not characterized and requires further exploration. To investigate that, we generated mice with Nrf2 knockdown specifically in MG to rigorously assess the role of endogenous Nrf2 activation in ischemic brain injury after stroke. Our results showed that MG-specific Nrf2 knockdown exacerbated ischemic brain injury after stroke. We found that Nrf2 knockdown altered MG phenotypes after stroke, in which increased frequency of inflammatory MG and decreased frequency of anti-inflammatory MG were detected in the ischemic brain. Moreover, we identified attenuated Nrf2/HO-1 axis activation led to increased CD68/IL-1β and suppressed CD206 expression in MG, resulting in aggravated inflammatory MG in MG-specific Nrf2 knockdown mice after stroke. Intriguingly, using type II diabetic preclinical models, we revealed that diabetic mice exhibited attenuated Nrf2/HO-1 axis activation in MG and exacerbated ischemic brain injury after stroke that phenocopy mice with MG-specific Nrf2 knockdown. Finally, the induction of exogenous Nrf2/HO-1 axis activation in MG through pharmacological approaches ameliorated ischemic brain injury in diabetic mice. In conclusion, our findings provide cellular and molecular insights demonstrating ischemia-induced endogenous Nrf2/HO-1 axis activation modulates MG phenotypes and restrains ischemic brain injury. These results further strengthen the therapeutic potential of targeting Nrf2/HO-1 axis in MG for the treatment of ischemic stroke and diabetic stroke.

Therapeutic Effects of Metformin on Central Nervous System Diseases: A Focus on Protection of Neurovascular Unit.

Metformin is one of the most commonly used oral hypoglycemic drugs in clinical practice, with unique roles in neurodegeneration and vascular lesions. Neurodegeneration and vasculopathy coexist in many diseases and typically affect the neurovascular unit (NVU), a minimal structural and functional unit in the central nervous system. Its components interact with one another and are indispensable for maintaining tissue homeostasis. This review focuses on retinal (diabetic retinopathy, retinitis pigmentosa) and cerebral (ischemic stroke, Alzheimer's disease) diseases to explore the effects of metformin on the NVU. Metformin has a preliminarily confirmed therapeutic effect on the retinal NUV, affecting many of its components, such as photoreceptors (cones and rods), microglia, ganglion, Müller, and vascular endothelial cells. Since it rapidly penetrates the blood-brain barrier (BBB) and accumulates in the brain, metformin also has an extensively studied neuronal protective effect in neuronal diseases. Its mechanism affects various NVU components, including pericytes, astrocytes, microglia, and vascular endothelial cells, mainly serving to protect the BBB. Regulating the inflammatory response in NVU (especially neurons and microglia) may be the main mechanism of metformin in improving central nervous system related diseases. Metformin may be a potential drug for treating diseases associated with NVU deterioration, however, more trials are needed to validate its timing, duration, dose, clinical effects, and side effects.

Tanshinone IIA Against Cerebral Ischemic Stroke and Ischemia-Reperfusion Injury: A Review of the Current Documents.

Stroke is a well-known neurological disorder that carries significant morbidity and mortality rates worldwide. Cerebral Ischemic Stroke (CIS), the most common subtype of stroke, occurs when thrombosis or emboli form elsewhere in the body and travel to the brain, leading to reduced blood perfusion. Cerebral Ischemia/Reperfusion Injury (CIRI) is a common complication of CIS and arises when blood flow is rapidly restored to the brain tissue after a period of ischemia. The therapeutic approaches currently recognized for CIS, such as thrombolysis and thrombectomy, have notable side effects that limit their clinical application. Recently, there has been growing interest among researchers in exploring the potential of herbal agents for treating various disorders and malignancies. One such herbal agent with medicinal applications is tanshinone IIA, an active diterpene quinone extracted from Salvia miltiorrhiza Bunge. Tanshinone IIA has shown several pharmacological benefits, including anti-inflammatory, antioxidant, anti-apoptotic, and neuroprotective properties. Multiple studies have indicated the protective role of tanshinone IIA in CIS and CIRI. This literature review aims to summarize the current findings regarding the molecular mechanisms through which this herbal compound improves CIS and CIRI.

Integrative microbiomics, proteomics and lipidomics studies unraveled the preventive mechanism of Shouhui Tongbian Capsules on cerebral ischemic stroke injury

Ethnopharmacological relevanceCerebral ischemic stroke (CIS) is one of the most important factors leading to death and disability, which seriously threaten the survival and health of patients. The intentional flora and its derived metabolites are demonstrated to play vital roles in the physiology and onset of CIS. Shouhui Tongbian Capsules (SHTB), a Traditional Chinese Medicine, could regulate gut microbiota and metabolites. Study has found that SHTB has protective effect on CIS, but the mechanism is still unclear. Aim of studyThis study was designed to evaluate the preventive effects and the mechanism of SHTB on CIS injury. Materials and methodsThe rats were pretreated with SHTB for 5 days, then the middle cerebral artery occlusion/reperfusion (MCAO/R) was established. Neurological deficit score, TTC staining, brain water content, H&E and Nissl staining were preformed to evaluate the preventive effects of SHTB on CIS. The Occludin and ZO-1 were analyzed to evaluate the blood-brain barrier (BBB). 16S rDNA sequencing and LC-ESI-MS/MS-based metabolomics profiling were performed to analyze the gut microbiota composition and short chain fatty acids (SCFAs) profile in gut. Serum lipopolysaccharide specific IgA antibody (LPS-SIgA) and diamine oxidase (DAO), as well as colon Claudin 5 and ZO-1 were analyzed to evaluate the intestinal barrier. Proteomics was used to evaluated the proteins profile in brain. Lipidomics were used to evaluate the brain SCFAs as well as medium and long chain fatty acids (MCFAs and LCFAs). Malondialdehyde (MDA), Total Superoxide dismutase (T-SOD), Glutathione (GSH), Glutathione peroxidase (GSH-Px), Catalase (CAT) and reactive oxygen species (ROS) were assayed to evaluate the oxidative stress in brain. Western blot was performed to evaluate the expression of PPARγ, Nrf2, SLC3A2, SCL7A11, GPX4, ACSL4 and LOX. ResultsSHTB prevented rats from MCAO/R injury, which was confirmed by lower cerebral infarct rate, brain water content, neurological deficit score and nissl body loss, and improved brain pathology. Meanwhile, SHTB upregulated the expression of ZO-1 and Occludin to maintain the integrity of BBB. 16S rDNA sequencing and LC-ESI-MS/MS-based targeted metabolomics found that SHTB increased the abundance of gut microbiota, regulated the numbers of intestinal bacteria to increase the production of Acetic acid, Propionic acid, and Butyric acid, as well as decrease the production of Valeric acid and Hexanoic acid in the gut. Meanwhile, SHTB improved the intestinal barrier by upregulating the protein levels of Claudin 5 and ZO-1, which was confirmed by low concentrations of LPS-SIgA and DAO in serum. Multi omics and spearman correlation analysis indicated that SHTB regulated the abundance of Escherichia-Shigella and Lactobacillus to increase Acetic acid, Propionic acid, and Butyric acid to induce the expression of PPARγ, thereby regulating fatty acid metabolism and degradation, improving lipid metabolism disorders, downregulating lipid oxidative stress, inhibiting ferroptosis, and alleviating brain injury. ConclusionThis study confirmed that SHTB improved the disturbance of fatty acid metabolism in brain tissue by regulating gut microbiota and the production of fecal SCFAs to inhibit ferroptosis caused by lipid oxidative stress and prevent CIS injury, which provided a potential candidate drug for the prevention of CIS.

Modeling of Cerebral Ischemic Stroke in Conscious Rats via Arterial Air Embolization.

The etiological factor of cerebral ischemia in the vast majority of cases is vascular embolism. In the present study we investigated embolism caused by atmospheric air bubbles injected into the internal carotid artery of conscious rats. Immediately after embolism modeling, behavioral abnormalities were observed in the animals, and after 24 h, foci of brain damage were detected. The death of animals was observed within 5 days after embolism. The proposed experimental model of cerebral ischemia in conscious rats is more relevant and better corresponds to real conditions than the model on narcotized animals and allows to perform physiological tests immediately after modeling.

Effects of Sildenafil on Cognitive Function Recovery and Neuronal Cell Death Protection after Transient Global Cerebral Ischemia in Gerbils.

Cerebral ischemic stroke is a major cause of death worldwide due to brain cell death resulting from ischemia-reperfusion injury. However, effective treatment approaches for patients with ischemic stroke are still lacking in clinical practice. This study investigated the potential neuroprotective effects of sildenafil, a phosphodiesterase-5 inhibitor, in a gerbil model of global brain ischemia. We investigated the effects of sildenafil on the expression of glial fibrillary acidic protein and aquaporin-4, which are markers related to astrocyte activation and water homeostasis, respectively. Immunofluorescence analysis showed that the number of cells co-expressing these markers, which was elevated in the ischemia-induced group, was significantly reduced in the sildenafil-treated groups. This suggests that sildenafil may have a potential mitigating effect on astrocyte activation induced by ischemia. Additionally, we performed various behavioral tests, including the open-field test, novel object recognition, Barnes maze, Y-maze, and passive avoidance tests, to evaluate sildenafil's effect on cognitive function impaired by ischemia. Overall, the results suggest that sildenafil may serve as a neuroprotective agent, potentially alleviating delayed neuronal cell death and improving cognitive function impaired by ischemia.

Risk factors for urinary retention requiring catheterization after ischemic middle cerebral artery stroke

Purpose: Urinary retention is common in patients with ischemic stroke. Therefore, we aimed to identify the risk factors for urinary retention requiring indwelling urinary catheters (IUCs) in patients with acute middle cerebral artery (MCA) ischemic stroke. Materials and methods: We retrospectively reviewed the medical records of all patients with acute MCA infarction who required admission to the neurological intensive care unit between January 2009 and December 2019 at our tertiary hospital. Patients who did not need IUCs before the stroke but required them after the stroke were included. Multivariate logistic regression analysis was used to identify the risk factors associated with urinary retention requiring IUCs after 7, 14, 21, and 28 days of stroke. Results: A total of 104 patients were included in this study. Among them, 75 (72.2%), 65 (62.5%), 52 (50.0%), and 44 (42.3%) patients required IUCs 7, 14, 21, and 28 days after stroke, respectively. Multivariate logistic regression analysis showed that hypertension was associated significantly with the requirement of IUCs 7 days (odds ratio [OR] = 2.987; P = 0.026) and 14 days (OR = 3.047; P = 0.021) after acute stroke. Furthermore, a higher National Institutes of Health Stroke Scale score was associated significantly with the requirement for IUCs 14 days (OR = 1.096; P = 0.030) and 21 days (OR = 1.091; P = 0.027) after stroke. Conclusion: Hypertension and higher National Institutes of Health Stroke Scale scores are associated significantly with urinary retention requiring IUCs after acute ischemic MCA stroke and could serve as risk factors for voiding dysfunction in this population.

Macrophage Scavenger Receptor 1 attenuates ischemic white matter injury via HRH1-mediated microglial phagocytosis

The removal of axonal and myelin debris by macrophages is crucial for safeguarding nerves and facilitating functional recuperation in cerebral ischemic stroke. However, the physiological function of macrophage scavenger receptor 1 (MSR1) in ischemic white matter injury remains poorly de-fined. In this study, we observed an elevation in Msr1 expression levels in mice with experimental cerebral ischemic stroke. Msr 1-deficient (Msr1-/-) mice exhibited exacerbated behavioral deficits and aggravated white matter injury after ischemic stroke. Furthermore, the overexpression of Msr1 led to an increase in the phosphorylation of Akt via Hrh1, which in turn expedited the clearance of myelin debris through the PI3K/AKT pathway. In conclusion, our findings underscore the essential role of MSR1 in microglial phagocytosis and its ability to mitigate ischemic white matter injury in cerebral ischemic stroke.

Effects of Panax notoginseng saponins on alleviating low shear induced endothelial inflammation and thrombosis via Piezo1 signalling

Ethnopharmacological relevancePanax notoginseng saponins (PNS) are the major effective components of Panax notoginseng (burk) F.H.Chen which is one of the classic promoting blood circulation herbs in traditional Chinese medicine. PNS is widely used in China for the treatment of cerebral ischemic stroke. Pathological low shear stress is a causal factor in endothelial inflammation and thrombosis. However, the mechanism of PNS against low shear related endothelial inflammation is still unclear. Aim to the studyThis study aims to investigate the effects of PNS against endothelial inflammation induced by low shear stress and to explore the underlying mechanical and biological mechanisms. Materials and methodsMouse model of carotid partial ligation for inducing low endothelial shear stress was established, the pharmacodynamic effect and mechanism of PNS against endothelial inflammation induced by low shear stress through Piezo1 were explored. Yoda1-evoked Piezo1 activation and expression in human umbilical vein endothelial cells (HUVECs) were determined at static condition. Microfluidic channel systems were used to apply shear stress on HUVECs and Piezo1 siRNA HUVECs to determine PECAM-1, p-YAP and VCAM-1 expression. And platelet rich plasma (PRP) was introduced to low shear treated endothelial cells surface to observe the adhesion and activation by fluorescence imaging and flowcytometry. ResultsPNS attenuated endothelial inflammation and improved blood flow in a reasonable dose response pattern in carotid partial ligation mouse model by influencing Piezo1 and PECAM-1 expression, while suppressing yes-associated protein (YAP) nuclear translocation. We found Piezo1 sensed abnormal shear stress and transduced these mechanical signals by different pathways in HUVECs, and PNS relieved endothelial inflammation induced by low shear stress through Piezo1. We also found Piezo1 signalling has interaction with PECAM-1 under low shear stress, which were involved in platelets adhesion to endothelial cells. Low shear stress increased YAP nuclear translocation and increased VCAM-1 expression in HUVECs which might activate platelets. PNS inhibited low shear induced Piezo1 and PECAM-1 expression and YAP nuclear translocation in HUVECs, furthermore inhibited platelet adhesion and activation on dysfunctional endothelial cells induced by low shear stress. ConclusionPNS ameliorated endothelial inflammation and thrombosis induced by low shear stress through modulation of the Piezo1 channel, PECAM-1 expression, and YAP nuclear translocation. PNS might serve as a potential therapeutic candidate for ameliorating endothelial inflammation induced by abnormal blood shear stress.

Temporal and Spatial Dynamics of Ischemic Stroke Lesions after Acute Therapy: A Comprehensive Edema Assessment Using Combined 1H- and 23Na-MRI.

Ischemic cerebral stroke initiates a complex cascade of pathophysiological events, involving various forms of molecular shifts and edema. Early intervention is pivotal in minimizing tissue loss and improving clinical outcomes. This study explores the temporal and spatial evolution of tissue sodium concentration (TSC) in acute ischemic lesions after acute therapy using 23Na-MRI in addition to conventional 1H-MRI. Prospectively, from examined 58 patients with acute ischemic stroke with a combined 1H/23Na-MRI within 72 h of symptom onset after receiving acute therapy, 31 patients were included in the evaluation of this study. After co-registration of the 23Na-MRI images to the morphological 1H-MRI images, manual segmentation of the ischemic lesions was performed, and the ADC and TSC measurements were quantified and correlated with the time of onset and lesion volume. The mean TSC in ischemic lesions correlated positively with lesion volume (r = 0.52, p = 0.002) and showed a significant association with the time of stroke onset (r = 0.8, p < 0.001). Patients who were treated only with intravenous rtPA showed homogenous sodium signal intensity in the ischemic lesions, whereas the patients who received mechanical recanalization exhibited distinctive sodium signal intensity patterns with focal significant TSC differences. The integration of 1H- and 23Na-MRI provides a nuanced understanding of temporal and spatial changes due to different types of edema in ischemic stroke lesions following acute treatment. Further exploration of these findings may enhance our understanding of stroke pathophysiology and guide personalized therapeutic interventions.

Endovascular therapy versus best medical management in distal medium middle cerebral artery acute ischaemic stroke: a multinational multicentre propensity score-matched study

BackgroundThe efficacy of endovascular treatment (EVT) in acute ischaemic stroke due to distal medium vessel occlusion (DMVO) remains uncertain. Our study aimed to evaluate the safety and efficacy of EVT...

Mailuo Shutong pills inhibit neuroinflammation by regulating glucose metabolism disorders to protect mice from cerebral ischemia-reperfusion injury

Ethnopharmacological relevanceMailuo Shutong Pill (MLST), a traditional Chinese medicine (TCM), has been widely used for clearing heat and detoxifying, eliminating stasis and dredging meridians, dispelling dampness and diminishing swelling. Earlier study found that MLST could improve cerebral ischemic-reperfusion injury, however, the potential mechanism has not been well evaluated. Aim of studyIn this study, a well established and widely used mice model of middle cerebral artery occlusion/reperfusion (MCAO/R) was preformed to evaluate the protective function of MLST on cerebral ischemic-reperfusion injury and further discuss the potential pharmacological mechanisms. Materials and methodsChemical profiling of MLST was analyzed based on Ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry. ICR mice were challenged by MCAO/R surgery. The protective effect of MLST on MCAO/R injury was evaluated by neurological deficit score, cerebral infarct rate, brain water content, H&E and nissl staining. The blood-brain barrier (BBB) integrity was detected by Evans blue staining. The potential pharmacological mechanism of MLST in treating MCAO/R injury was further elucidated by the methods of proteomics, central carbon targeted metabolomics, as well as Western blot. Immunohistochemistry was used to detect the microglia infiltration, enzyme linked immunosorbent assay (ELISA) kit was explored to evaluate the content of IL-1β, TNF-α and IL-6 in brain tissue, and Western blot was used to detect proteins expression in brain tissue. ResultsA total of 76 chemical compounds have been determined in MLST. MLST effectively protected mice from MCAO/R injury, which was confirmed by lower neurological deficit score, cerebral infarct rate, brain water content and nissl body loss, and improved brain pathology. Meanwhile, MLST upregulated the expression of ZO-1, Occludin and Claudin 5 by downregulating the ratio of TIMP1/MMP9 to suppress the entrance of Evans blue to brain tissue, indicating that MLST maintained the integrity of BBB. Further studies indicated that MLST inhibited the inflammatory level of brain tissue by inhibiting microglia infiltration and downregulating NLRP3 inflammasome signaling pathway. The results of proteomics, Western blot, and central carbon targeted metabolomics confirmed that MLST regulated Glycolysis/Gluconogenesis, Pyruvate metabolism and TCA cycle in brain tissue of mice with MCAO/R. ConclusionMLST inhibits neuroinflammation by regulating glucose metabolism disorders to interfere with immune metabolism reprogramming and inhibit the NLRP3 inflammasome signaling pathway, and finally improve cerebral ischemia-reperfusion injury. This study confirms that MLST is a potential drug for treating Cerebral ischemic stroke.

Effects of "brain-gut coherence" method of acupuncture on motor function and intestinal microflora in the patients with cerebral ischemic stroke

To observe the clinical effect of "brain-gut coherence" method of acupuncture on cerebral ischemic stroke (CIS) and explore its action mechanism. A total of 82 patients with CIS were randomly divided into an observation group (41 cases, 3 cases dropped out, 2 cases discontinued) and a control group (41 cases, 4 cases dropped out, 2 cases excluded). The conventional basic treatment was administered in the two groups. Additionally, in the observation group, "brain-gut coherence" method of acupuncture was delivered. The stimulating points included the parietal and temporal anterior oblique line on the affected side, Zhongwan (CV 12), Guanyuan (CV 4), and bilateral Tianshu (ST 25), Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39). In the control group, the routine acupuncture was operated at Baihui (GV 20), Yintang (GV 24+), bilateral Fengchi (GB 20) and Zusanli (ST 36), and Hegu (LI 4), Jianyu (LI 15), Quchi (LI 11), Waiguan (TE 5), Futu (ST 32), Sanyinjiao (SP 6) and Taichong (LR 3) on the affected side. Acupuncture stimulation lasted 30 min each time, once daily, and for 5 days a week. The intervention for 4 weeks was required. The scores of Fugl-Meyer assessment scale (FMA), Berg balance scale (BBS) and the modified Barthel index (MBI), as well as the score of gastrointestinal symptoms were compared before and after treatment in the two groups. The neutrophil count (NUE) and the content of the serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) were detected before and after treatment in the two groups. Using 16S rRNA gene sequencing, the structure and relative abundance of intestinal microflora was detected before and after treatment; and with the enzyme linked immunosorbent assay (ELISA) adopted, the levels of intestinal fatty acid-binding protein (iFABP), D-lactate (D-LA), lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP), tumor necrosis factor-α(TNF-α), interleukin (IL)-1β and IL-6 in the serum were detected before and after treatment in the two groups. After treatment, the scores of FMA, BBS and MBI were increased (P<0.05), and the scores of gastrointestinal symptoms were decreased (P<0.05) compared with those before treatment in the two groups. Compared with the control group, the scores of FMA, BBS and MBI were higher (P<0.05) and the score of gastrointestinal symptoms was lower (P<0.05) in the observation group after treatment. NEU and the content of serum NT-proBNP were reduced in the two groups (P<0.05), and the content of serum NT-proBNP in the observation group was lower than that of the control group (P<0.05) after treatment. Chao1, Ace, Sobs and Shannon indexes were increased after treatment compared with those before treatment in the two groups (P<0.05); and these indexes in the observation group were higher when compared with the control group (P<0.05). After treatment, the relative abundance of Bacteroidaceae, Enterobacteriaceae, Oscillospiraceae, Streptococcaceae and Sutterellaceae was reduced in comparison with that before treatment in the two groups (P<0.05); and the relative abundance of these microflora was lower in the observation group when compared with the control group (P<0.05). After treatment, the relative abundance of Lachnospiraceae, Ruminococcaceae, Bifidobacteriaceae and Coriobacteriaceae was increased in comparison with that before treatment in the two groups (P<0.05); and the relative abundance of these microflora was elevated in the observation group when compared with the control group (P<0.05). After treatment, the levels of iFABP, D-LA, LPS, LBP, TNF-α, IL-1β and IL-6 were reduced when compared with those before treatment in the two groups (P<0.05), and these levels of the observation group were lower than those of the control group (P<0.05). "Brain-gut coherence" method of acupuncture can improve the motor function and gastrointestinal function of the patients with cerebral ischemic stroke, which may be related to modulating the structure of intestinal microflora, alleviating inflammatory reactions and accelerating the intestinal barrier repair.

Analysis of the Role of Problem-Based Independent Learning Model in Teaching Cerebral Ischemic Stroke First Aid in Emergency Medicine

Objective: To analyze the effect of using a problem-based (PBL) independent learning model in teaching cerebral ischemic stroke (CIS) first aid in emergency medicine. Methods: 90 interns in the emergency department of our hospital from May 2022 to May 2023 were selected for the study. They were divided into Group A (45, conventional teaching method) and Group B (45 cases, PBL independent learning model) by randomized numerical table method to compare the effects of the two groups. Results: The teaching effect indicators and student satisfaction scores in Group B were higher than those in Group A (P &lt; 0.05). Conclusion: The use of the PBL independent learning model in the teaching of CIS first aid can significantly improve the teaching effect and student satisfaction.

Relationship Between the Gut Microbiota and Neurological Deficits in Patients With Cerebral Ischemic Stroke

Objective The aim of the paper was to investigate the composition and structure of intestinal flora in patients with cerebral ischemic stroke (CIS), and to investigate the relationship between gut microbiota (GM) and different levels of stroke severity. Methods In this study, 47 CIS patients (16 mild, 21 moderate, and 10 severe) and 15 healthy controls were included. General information, clinical data, and behavioral scores of the enrolled subjects were collected. Deoxyribonucleic acid in fecal intestinal flora was extracted and detected using high-throughput Illumina 16S ribosomal ribonucleic acid sequencing technology. Finally, the correlation between the community composition of intestinal microbiota and National Institutes of Health Stroke Scale (NIHSS) score in CIS patients was analyzed. Results Compared with healthy controls, there was no statistically significant difference in Alpha diversity among CIS patients, but the principal coordinate analysis showed significant differences in the composition of the GM among stroke patients with different degrees of severity and controls. In CIS patients, Streptococcus was significantly enriched, and Eshibacter—Shigella, Bacteroides, and Agathobacter were significantly down-regulated (P < .05). In addition, the relative abundance of Blautia was negatively correlated with the NIHSS score. Conclusions Our results show that different degrees of CIS severity exert distinct effects on the intestinal microbiome. This study reveals the intestinal microecological changes after brain injury from the perspective of brain–gut axis. Intestinal microorganisms not only reveal the possible pathological process and indicate the severity of neurologic impairment, but also make targeted therapy possible for CIS patients.

Sovateltide in cerebral ischaemic stroke: a profile of its use

Sovateltide in cerebral ischaemic stroke: a profile of its use