Embolic Middle Cerebral Artery Research Articles

Exploring the relationship between embolic acute stroke distribution and supra-aortic vessel patency: key findings from an in vitro model study

BackgroundWe investigated differences in intracranial embolus distribution through communicating arteries in relation to supra-aortic vessel (SAV) patency.MethodsFor this experimental analysis, we created a silicone model of the extracranial and intracranial...

Role of Micro Ribonucleic Acid-124 in Protecting Against Nerve Injury After Cerebral Ischemia/Reperfusion

The researchers aimed to evaluate micro ribonucleic acid (miR)-124 for its protective role in nerve injury in rats following cerebral ischemia/reperfusion. A focal middle cerebral artery embolism model was constructed. Compared with sham operation group, model and miR-124 NC groups had significantly increased miR-124 expression, neurobehavioral score, malondialdehyde (MDA) content, brain infarct volume, and apoptosis rate, elevated expression levels of Bcl-2- associated X (Bax) protein as well as cleaved caspase-3, 8 and 9, attenuated activity of superoxide dismutase (SOD), and lowered expression of B-cell lymphoma 2 (Bcl-2) (P<0.01). By contrast to those in model and miR-124 NC groups, Bcl- 2 expression rose, miR-124 expression, neurobehavioral score, brain infarct volume percentage and apoptosis rate reduced, Bax, cleaved caspase-3, 8 and 9 expression levels declined, SOD activity enhanced, and MDA content in miR- 124 mimic group dropped (P<0.01). In conclusion, miR-124 protects rats from nerve injury after cerebral ischemia/ reperfusion by improving the antioxidant capacity and regulating the expressions of apoptosis-associated proteins.

Unusually elongated superior thyroid cornu associated with recurrent cerebral embolisms.

The superior thyroid cornu (STC) is a normal anatomic structure that forms part of the thyroid cartilage. Here, we report a patient with unusually elongated and ossified STC that might result in recurrent cerebral embolisms. During a second endovascular therapy for recurrent middle cerebral artery embolism, a segment with an irregular filling defect was noted in the internal carotid artery (ICA), at the C1 level. This defect was unnoticed during the initial endovascular procedure. Three-dimensional computed tomography angiography performed after the second endovascular procedure revealed an ICA segment located between the STC and C1 with a tortuous course and irregular wall of the ICA. Therefore, we assumed that STC compression of the ICA could have resulted in thrombus formation at the site and consequent cerebral embolism. The STC should be considered a structure responsible for cerebral embolism. Careful evaluation of the entire ICA course is imperative prior to performing an endovascular thrombectomy for acute embolic occlusion of the middle cerebral artery.

The Water Extract of Rhubarb Prevents Ischemic Stroke by Regulating Gut Bacteria and Metabolic Pathways.

Rhubarb (RR), Chinese name Dahuang, is commonly used in the treatment of ischemic stroke (IS). However, its potential mechanism is not fully elucidated. This study intended to verify the effect of RR on IS and investigate the possible mechanism of RR in preventing IS. IS in male rats was induced by embolic middle cerebral artery occlusion (MCAO) surgery, and drug administration was applied half an hour before surgery. RR dramatically decreased the neurological deficit scores, the cerebral infarct volume, and the cerebral edema rate, and improved the regional cerebral blood flow (rCBF) and histopathological changes in the brain of MCAO rats. The 16S rRNA analysis showed the harmful microbes such as Fournierella and Bilophila were decreased, and the beneficial microbes such as Enterorhabdus, Defluviitaleaceae, Christensenellaceae, and Lachnospira were significantly increased, after RR pretreatment. 1H-nuclear magnetic resonance (1H-NMR) was used to detect serum metabolomics, and RR treatment significantly changed the levels of metabolites such as isoleucine, valine, N6-acetyllysine, methionine, 3-aminoisobutyric acid, N, N-dimethylglycine, propylene glycol, trimethylamine N-oxide, myo-inositol, choline, betaine, lactate, glucose, and lipid, and the enrichment analysis of differential metabolites showed that RR may participate in the regulation of amino acid metabolism and energy metabolism. RR exerts the role of anti-IS via regulating gut bacteria and metabolic pathways.

Mechanism of scutellarin inhibition of astrocyte activation to type A1 after ischemic stroke

ObjectiveThe aim of this study was to investigate the effects of scutellarin on the activation of astrocytes into the A1 type following cerebral ischemia and to explore the underlying mechanism. MethodsIn vivo, a mouse middle cerebral artery wire embolism model was established to observe the regulation of astrocyte activation to A1 type by scutellarin, and the effects on neurological function and brain infarct volume. In vitro, primary astrocytes were cultured to establish an oxygen-glucose deprivation model, and the mRNA and protein expression of C3, a specific marker of A1-type astrocytes pretreated with scutellarin, were examined. The neurons were cultured in vitro to detect the toxic effects of ischemia-hypoxia-activated A1 astrocyte secretion products on neurons, and to observe whether scutellarin could reduce the neurotoxicity of A1 astrocytes. To validate the signaling pathway-related proteins regulated by scutellarin on C3 expression in astrocytes. ResultsThe results showed that scutellarin treatment reduced the volume of cerebral infarcts and attenuated neurological deficits in mice caused by middle cerebral artery embolism. Immunofluorescence and Western blot showed that treatment with scutellarin down-regulated middle cerebral artery embolism and OGD/R up-regulated A1-type astrocyte marker C3. The secretory products of ischemia-hypoxia-activated A1-type astrocytes were toxic to neurons and induced an increase in neuronal apoptosis, and astrocytes treated with scutellarin reduced the toxic effects on neurons. Further study revealed that scutellarin inhibited the activation of NF-κB signaling pathway and thus inhibited the activation of astrocytes to A1 type.

A Cerebral Embolism Caused by a Malignant Peripheral Nerve Sheath Tumor in a Patient with Neurofibromatosis Type 1.

A 31-year-old man with neurofibromatosis type 1 (NF-1) had undergone resection of a malignant peripheral nerve sheath tumor (MPNST) on the buttock 3 months previously. He subsequently underwent mechanical thrombectomy for a hyperacute left middle cerebral artery embolism. Histopathologically, the emboli comprised neurofilament-positive pleomorphic tumor cells with geographic necrosis and conspicuous mitosis and were identified as MPNST. The patient died of respiratory failure due to lung MPNST metastasis on day 15 of hospitalization. To our knowledge, this is the first report of a spontaneous cerebral embolism due to MPNST in a NF-1 patient.

An Ultrasmall Cu/Cu2O Nanoparticle-Based Diselenide-Bridged Nanoplatform Mediating Reactive Oxygen Species Scavenging and Neuronal Membrane Enhancement for Targeted Therapy of Ischemic Stroke.

Ischemic stroke is one of the major causes of death and disability worldwide, and an effective and timely treatment of ischemic stroke has been a challenge because of the narrow therapeutic window and the poor affinity with thrombus of the thrombolytic agent. In this study, rPZDCu, a multifunctional nanoparticle (NP) with the effects of thrombolysis, reactive oxygen species (ROS) scavenging, and neuroprotection, was synthesized based on an ultrasmall Cu4.6O NP, the thrombolytic agent rt-PA, and docosahexaenoic acid (DHA), which is a major component of the neuronal membrane. rPZDCu showed strong thrombus-targeting ability, which was achieved by the platelet cell membrane coating on the NP surface, and a good thrombolytic effect in both the common carotid artery clot model and embolic middle cerebral artery occlusion (MCAO) model of rats. Furthermore, rPZDCu exhibited a good escape from the phagocytosis of macrophages, effective promotion of the polarization of microglia, and efficient recovery of neurobiological and behavioral functions in the embolic MCAO model of rats. This is a heuristic report of (1) the Cu0/Cu+ NP for the treatments of brain diseases, (2) the integration of DHA and ROS scavengers for central nervous system therapies, and (3) diselenide-based ROS-responsive NPs for ischemic stroke treatments. This study also offers an example of cell membrane-camouflaged stimuli-responsive nanomedicine for brain-targeting drug delivery.

Application of Sofia Plus catheter tip shaping in the treatment of acute middle cerebral artery occlusion: A case control study.

To explore the safety and efficacy of Sofia Plus distal access catheter tip shaping for treatment of acute middle cerebral artery embolism. This single-center retrospective study involved patients eligible for acute embolic middle cerebral artery occlusion from January 2020 to October 2021. They were divided into a shaping and non-shaping group according to whether the Sofia Plus catheter tip was shaped intraoperatively. Baseline data, preoperative Alberta Stroke Program Early Computed Tomography (ASPECT) score, National Institutes of Health Stroke Scale (NIHSS) score, onset-to-admission time, admission-to-puncture time, Sofia Plus-clot time, puncture-to-reperfusion time, surgical approach, and use of a stent for rescue thrombectomy were compared between the 2 groups. Postoperative symptomatic intracerebral hemorrhage and the modified Rankin scale score at the 90-day follow-up were observed. In total, 54 patients were enrolled in this study (shaping group, 26 patients; non-shaping group, 28 patients). Their mean age was 64.8 ± 14.6 years, and the proportion of men was 68.5% (37/54). Successful recanalization was achieved in all patients. There were no differences in the baseline data (age, sex, history, pre-admission ASPECT score, or NIHSS score) between the shaping and non-shaping groups. Patients treated with a shaped Sofia Plus catheter had a shorter Sofia Plus-clot time [median (25th, 75th percentile: 4 (4, 7) vs 10.5 (5.25, 14) min, P = .006] and puncture-to-reperfusion time [16.5 (12, 30.5) vs 26 (16.25, 38.25) min, P = .036]. There were significant differences in the surgical approaches between the 2 groups. The rates of a favorable outcome (57.7% vs 64.3%, P = .62) and postoperative symptomatic intracerebral hemorrhage (7.7% vs 3.6%, P = .60) were not significantly different between the groups. Sofia Plus catheter tip shaping improved catheter trafficability and reduced the operative time. It was safe and effective for treatment of acute middle cerebral artery thrombotic occlusion.

Treatment of stroke in aged male and female rats with Vepoloxamer and tPA reduces neurovascular damage.

Male and female Wistar rats at 18 months of age were subjected to embolic middle cerebral artery occlusion and treated either with monotherapy of tPA or Vepoloxamer, a combination of these two agents, or saline at 4 h after stroke onset. Neurological outcomes were evaluated with a battery of behavioral tests including adhesive removal, foot-fault, and modified neurological severity score tests at 1 and 7 days after stroke onset, followed by histopathological analysis of infarct volume. Residual clot size and vascular patency and integrity were analyzed. The combination treatment with Vepoloxamer and tPA significantly reduced infarct volume and neurological deficits in male and female rats compared to rats treated with saline and the monotherapies of tPA and Vepoloxamer. While Vepoloxamer monotherapy moderately reduced neurological deficits, monotherapies with tPA and Vepoloxamer failed to reduce infarct volume compared to saline treatment. Furthermore, the combination treatment with tPA and Vepoloxamer accelerated thrombolysis, reduced ischemia and tPA-potentiated microvascular disruption, and concomitantly improved cerebrovascular integrity and perfusion in the male ischemic rats. Combination treatment with tPA and Vepoloxamer at 4 h after stroke onset effectively reduces ischemic neurovascular damage by accelerating thrombolysis and reducing ischemia and tPA potentiated side effects in the aged rats. This funding suggests that the combination treatment with tPA and Vepoloxamer represents a promising strategy to potentially apply to the general population of stroke patients.

Study on alleviating neuroinflammatory injury in ischemic stroke rats by electrical stimulation with scalp acupuncture based on IFN-γ mediated JAK/STAT1 signaling pathway

To explore the molecular mechanism of electrical stimulation with scalp acupuncture (ESA) in alleviating neuroinflammatory injury in ischemic stroke rats based on interferon γ (IFN-γ)-mediated Janus kinase/signal transduction and transcriptional activator 1 (JAK/STAT1) signaling pathway. Fifty-six SD rats aged 7 weeks were randomly divided into normal, model, ESA and inhibitor groups, with 14 rats in each group. The middle cerebral artery embolization rat model was established by means of thread embolization. Rats in the inhibitor group were intraperitoneally injected with the inhibitor PJ34 (5 mg/mL, 25 mg/kg) once a day for 7 days. Rats in the ESA group were treated at bilateral anterior parietotemporal slash (MS6) with ESA (2 Hz/100 Hz, 1 mA), 30 min a day for 7 days. Before and after interventions, the neurological deficit score and neurobehavioral score were evaluated. The percentage of cerebral infarction volume was detected by TTC staining. The positive expressions of interleukin (IL)-6 and IL-10 in cerebral cortex were detected by immunohistochemistry. The protein expression levels of IFN-γ, JAK1, JAK2 and phosphorylated (p)-STAT1 in rats cerebral cortex were detected by Western blot. Compared with the normal group, the neurological deficit score, neurobehavioral score, the percentage of cerebral infarction volume, the expression levels of IL-6, IFN-γ, JAK1, JAK2 and p-STAT1 in cerebral cortex were increased (P<0.01), while the expression level of IL-10 was decreased (P<0.01) in the model group. Compared with the model group, the neurological deficit score and neurobehavioral score after treatment were significantly decreased (P<0.01), the percentage of cerebral infarction volume was decreased (P<0.01), the expression levels of IL-6, IFN-γ, JAK1, JAK2 and p-STAT1 in cerebral cortex were decreased (P<0.01), while the expression level of IL-10 was increased (P<0.01) in the ESA and inhibitor groups. ESA was superior to inhibitors in improving neurological deficit score and down-regulating p-STAT1 expression (P<0.05, P<0.01), and was inferior to inhibitor in reducing the percentage of cerebral infarction volume as well as down-regulating IFN-γ and JAK1 (P<0.01, P<0.05). Down-regulating the expression of IFN-γ and inhibiting the activity of JAK/STAT1 signaling pathway may be one of the mechanisms by which ESA alleviates neuroinflammatory injury in ischemic stroke rats.

Enhanced Cerebroprotection of Xenon-Loaded Liposomes in Combination with rtPA Thrombolysis for Embolic Ischemic Stroke.

Xenon (Xe) has shown great potential as a stroke treatment due to its exceptional ability to protect brain tissue without inducing side effects. We have previously developed Xe-loaded liposomes for the ultrasound-activated delivery of Xe into the cerebral region and demonstrated their therapeutic efficacy. At present, the sole FDA-approved thrombolytic agent for stroke treatment is recombinant tissue plasminogen activator (rtPA). In this study, we aimed to investigate the potential of combining Xe-liposomes with an intravenous rtPA treatment in a clinically relevant embolic rat stroke model. We evaluated the combinational effect using an in vitro clot lysis model and an in vivo embolic middle cerebral artery occlusion (eMCAO) rat model. The treatment groups received intravenous administration of Xe-liposomes (20 mg/kg) at 2 h post-stroke onset, followed by the administration of rtPA (10 mg/kg) at either 2 or 4 h after the onset. Three days after the stroke, behavioral tests were conducted, and brain sections were collected for triphenyltetrazolium chloride (TTC) and TUNEL staining. Infarct size was determined as normalized infarct volume (%). Both in vitro and in vivo clot lysis experiments demonstrated that Xe-liposomes in combination with rtPA resulted in effective clot lysis comparable to the treatment with free rtPA alone. Animals treated with Xe-liposomes in combination with rtPA showed reduced TUNEL-positive cells and demonstrated improved neurological recovery. Importantly, Xe-liposomes in combination with late rtPA treatment reduced rtPA-induced hemorrhage, attributing to the reduction of MMP9 immunoreactivity. This study demonstrates that the combined therapy of Xe-liposomes and rtPA provides enhanced therapeutic efficacy, leading to decreased neuronal cell death and a potential to mitigate hemorrhagic side effects associated with late rtPA treatment.

Procyanidins Alleviated Cerebral Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the Nrf2/HO-1 Signaling Pathway.

Procyanidins (PCs), which are organic antioxidants, suppress oxidative stress, exhibit anti-apoptotic properties, and chelate metal ions. The potential defense mechanism of PCs against cerebral ischemia/reperfusion injury (CIRI) was investigated in this study. Pre-administration for 7 days of a PC enhanced nerve function and decreased cerebellar infarct volume in a mouse middle cerebral artery embolization paradigm. In addition, mitochondrial ferroptosis was enhanced, exhibited by mitochondrial shrinkage and roundness, increased membrane density, and reduced or absent ridges. The level of Fe2+ and lipid peroxidation that cause ferroptosis was significantly reduced by PC administration. According to the Western blot findings, PCs altered the expression of proteins associated with ferroptosis, promoting the expression of GPX4 and SLC7A11 while reducing the expression of TFR1, hence inhibiting ferroptosis. Moreover, the treatment of PCs markedly elevated the expression of HO-1 and Nuclear-Nrf2. The PCs' ability to prevent ferroptosis due to CIRI was decreased by the Nrf2 inhibitor ML385. Our findings showed that the protective effect of PCs may be achieved via activation of the Nrf2/HO-1 pathway and inhibiting ferroptosis. This study provides a new perspective on the treatment of CIRI with PCs.

Electroacupuncture alleviates cerebral ischemia injury in rats by regulating melatonin-NLRP3 and inhibiting pyroptosis

To investigate the mechanism of electroacupuncture in alleviating cerebral ischemia injury in cerebral ischemia-reperfusion rats by regulating melatonin - NOD-like receptor protein 3 (NLRP3) mediated pyroptosis. A total of 48 SD rats were randomly divided into sham operation group, model group, electroacupuncture (EA) group and EA +Luz group, with 12 rats in each group. The focal cerebral ischemia-reperfusion injury model was established by middle cerebral artery embolization. Rats of the EA group was treated with EA stimulation (4 Hz/20 Hz, 0.5 mA,20 min) at "Baihui" (GV20) and "Shenting" (GV24) once a day for 7 consecutive days; rats of EA+Luz group were given the same EA treatment and intraperitoneally administered melatonin receptor antagonist (luzindole, 30 mg/kg), once a day for 7 consecutive days. The neurological impairment was evaluated by Zea Longa score. The level of serum melatonin content at 12:00 and 24:00 was detected by ELISA. The percentage of cerebral infarction volume was evaluated by MRI of small animals. The apoptosis rate of nerve cells in cerebral cortex of infarct side was detected by TUNEL staining. The activation of microglia cells was detected by immunofluorescence staining. The expression levels of pyroptosis-related proteins NLRP3, Caspase-1 and interleukin (IL) -1β were detected by Western blot. Compared with the sham operation group, the neural function score was significantly increased (P<0.01); the melatonin content was significantly decreased at 24:00 (P<0.01); the percentage of cerebral infarction volume, apoptosis rate of nerve cells in cerebral cortex area of infarction side, the expressions of NLRP3, Caspase-1 and IL-1β proteins were significantly increased (P<0.01); and microglia cells were significantly activated in the model group.Compared with the model and EA +Luz groups, the nerve function score was significantly decreased (P<0.05); the percentage of cerebral infarction volume, the nerve cell apoptosis rate, the activation level of microglia cells, the expression levels of NLRP3, Caspase-1 and IL-1β were significantly decreased (P<0.01, P<0.05) in the EA group. Compared with the model and EA+Luz groups, the melatonin content at 24:00 was significantly increased (P<0.01, P<0.05) in the EA group. EA at GV20 and GV24 can reduce the neurolo-gical injury in cerebral ischemia reperfusion model rats, which may be related to regulating the expression of endogenous melatonin, inhibiting cell scorchification and reducing cerebral ischemia injury.

Carvedilol Reduces the Neuronal Apoptosis after Ischemic Stroke by Modulating Activator of Transcription 3 Expression in vitro

Cerebral ischemia is divided into local cerebral ischemia and diffuse cerebral ischemia. The etiology of localized cerebral ischemia includes middle cerebral artery embolism; stenosis, occlusion, or thrombosis of extracranial internal carotid artery or vertebral artery; and cerebral artery spasm. The causes of diffuse cerebral ischemia include cardiac arrest, hypotension, anemia, and hypoglycemia. However, the underlying mechanism is still unclear. In this study, we demonstrated that activator of transcription 3 (ATF3) is a hubgene in IS by bioinformatics analysis. The expression of ATF3 was increased in PC12 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ATF3 deficiency inhibited cell viability and induced cell apoptosis, whereas ATF3 overexpression showed the opposite role in cell viability and cell apoptosis. Moreover, Carvedilol as a compound targeting ATF3 also facilitated cell viability and reduced cell apoptosis. ATF3 deficiency retarded the increase in cell viability and inhibition of cell apoptosis in OGD/R-PC12 cells with Carvedilol treatment. Additionally, the decreased Bax and cleaved caspase-3 were released in OGD/R-PC12 cells with Carvedilol and siATF3 treatment, while Bcl-2 expression was inhibited in OGD/R-PC12 cells with Carvedilol and siATF3 treatment. In conclusion, Carvedilol may be a key compound targeting ATF3 in OGD/R-PC12 cells. Graphical : Carvedilol positively regulated cell viability and negatively regulated cell apoptosis in OGD/R-PC12 cells by inhibition of ATF3.

Pharmacological Characterization of a Novel Neuroactive Steroid Prodrug, NTS-104, and Its Neuroprotective Activity in Experimental Stroke Models.

Ischemic stroke affects about 700 000 patients per year in the United States, and to date, there are no effective pharmacological agents that promote recovery. Here, we studied the pharmacokinetics, pharmacodynamics, and efficacy of NTS-105, a novel neuroactive steroid, and NTS-104, a prodrug of NTS-105, in 2 models of ischemic stroke. The pharmacodynamics and pharmacokinetics of NTS-104/105 were investigated in naive and stroke rats, and models of embolic and transient middle cerebral artery occlusion were used to investigate the dose-related effects of NTS-104. All rats were randomly assigned into the experimental groups, and all outcome measurements were performed blindly. Blood plasma and brain pharmacokinetic analysis revealed that NTS-104 rapidly converted to NTS-105, which reached peak concentration at ≈1 hour after dosing and distributed similarly to normal and ischemic brains. NTS-104 administration 4 hours after embolic middle cerebral artery occlusion led to a dose-dependent improvement of neurological outcomes and a dose-dependent reduction of infarct volumes relative to vehicle-treated animals. A single dose level study confirmed that NTS-104 administered 4 hours after transient middle cerebral artery occlusion was also neuroprotective. Quantitative ELISA revealed that NTS-104 treatment resulted in time- and dose-dependent changes in AKT activation and cytokine levels within the ischemic brain, which included reductions of IL-6, VEGF, ICAM-1, IL-1β, MCP-1, RAGE, and GM-CSF. Time- and dose-dependent reductions in IL-6 and GM-CSF were also observed in the plasma along with an elevation of galectin-1. NTS-104 is a novel prodrug that converts to a novel neuroactive steroid, NTS-105, which improves functional outcomes in experimental ischemic stroke models.

Mechanism of Guanxinning against cerebral ischemia-reperfusion injury in mice based on transcriptomic analysis

Guanxinning, a modern Chinese medicine preparation composed of Salviae Miltiorrhizae Radix et Rhizoma and Chuanxiong Rhizoma, has the activities of activating blood circulation, resolving blood stasis, dredging vessels, and nourishing the heart. Clinical studies have demonstrated that Guanxinning has therapeutic effect on ischemic stroke, while the specific mechanism remains to be clarified. In this study, the potential mechanism of Guanxinning against cerebral ischemia-reperfusion injury in mice was explored and then verified in vitro. The mouse model of cerebral ischemia-reperfusion injury was established with middle cerebral artery embolization(MCAO) method. The pharmacological effects of Guanxinning on the model mice were investigated based on neurological function score, cerebral infarction area, pathological morphology, neuron injury, and apoptosis. The results showed that Guanxinning lowered neurological functional score, reduced cerebral infarction area, and ameliorated the histopathological morphology, neuronal damage, and apoptosis in the model mice. RNA samples were extracted from brain tissues and subjected to RNA sequencing(RNA-seq). The differentially expressed genes(DEGs) were screened with the thresholds of ■. GO function enrichment analysis and KEGG pathway enrichment analysis were performed for the 297 common DEGs, which indicated that Guanxinning may regulate the inflammatory response, oxidative stress response, energy metabolism, and apoptosis to treat cerebral ischemia-reperfusion injury in mice. Guanxinning exerted protective effect through inhibiting inflammation and reducing oxidative stress in hypoxia/reoxygenation injured SH-SY5 Y cells. Furthermore, Western blot indicated that Guanxinning down-regulated the protein levels of p-NF-κB p65 and p-p38 MAPK and up-regulated those of PPARγ and PGC-1α. The findings suggested that Guanxinning may inhibit inflammation and reduce oxidative stress by suppressing TNF signaling pathway and activating PPAR signaling pathway, thereby exerting the therapeutic effect on cerebral ischemia-reperfusion injury in mice. This study preliminarily reveals the mechanism of Guanxinning against cerebral ischemia-reperfusion injury and provides a basis for clinical application of Guanxinning.

Dental Pulp Stem Cell Therapy in Ischemic Stroke: A Meta-Analysis of Preclinical Studies

ObjectiveMore preclinical research evidence has shown that dental pulp stem cells (DPSCs) transplantation is expected to promote the recovery of ischemic stroke (IS), but it still lacks an evidence-based analysis. The purpose of this study was to investigate the effects of DPSCs on neurological function and infarct size in Sprague-Dawley (SD) rats with middle cerebral artery embolization (MCAO). MethodsAccording to PRISMA guidelines, the preclinical study of DPSCs in the treatment of IS was screened according to the inclusion and exclusion criteria, and the relevant data and quality were evaluated by two independent researchers; A meta-analysis of histological and behavioral results was performed. ResultsSeven studies were finally included, with quality evaluation scores ranging from 8 to 9. Four articles reported modified Neurological Severity Scores (mNSS), three studies reported rotarod test, and six studies reported infarct volume. Meta-analysis showed that the mNSS score decreased by 1.17 times, the rotarod test increased by 1.11 times and the volume of cerebral infarction decreased by 1.91 times in the DPSC group compared with the blank control group. ConclusionTransplantation of DPSCs can significantly improve the neurological function of ischemic stroke and reduce the infarct volume.

J147 Reduces tPA-Induced Brain Hemorrhage in Acute Experimental Stroke in Rats.

Background and purposeJ147, a novel neurotrophic compound, was originally developed to treat aging-associated neurological diseases. Based on the broad spectrum of cytoprotective effects exhibited by this compound, we investigated whether J147 has cerebroprotection for acute ischemic stroke and whether it can enhance the effectiveness of thrombolytic therapy with tissue plasminogen activator (tPA).MethodsRats were subjected to transient occlusion of the middle cerebral artery (tMCAO) by insertion of an intraluminal suture or embolic middle cerebral artery occlusion (eMCAO), and treated intravenously with J147 alone or in combination with tPA.ResultsWe found that J147 treatment significantly reduced infarct volume when administered at 2 h after stroke onset in the tMCAO model, but had no effect in eMCAO without tPA. However, combination treatment with J147 plus tPA at 4 h after stroke onset significantly reduced infarct volume and neurological deficits at 72 h after stroke compared with saline or tPA alone groups in the eMCAO model. Importantly, the combination treatment significantly reduced delayed tPA-associated brain hemorrhage and secondary microvascular thrombosis. These protective effects were associated with J147-mediated inhibition of matrix metalloproteinase-9 (MMP9), 15-lipoxygenase-1, and plasminogen activator inhibitor (PAI) expression in the ischemic hemispheres (predominantly in ischemic cerebral endothelium). Moreover, the combination treatment significantly reduced circulating platelet activation and platelet-leukocyte aggregation compared with saline or tPA alone groups at 24 h after stroke, which might also contribute to reduced microvascular thrombosis and neuroinflammation (as demonstrated by reduced neutrophil brain infiltration and microglial activation).ConclusionOur results demonstrate that J147 treatment alone exerts cerebral cytoprotective effects in a suture model of acute ischemic stroke, while in an embolic stroke model co-administration of J147 with tPA reduces delayed tPA-induced intracerebral hemorrhage and confers cerebroprotection. These findings suggest that J147-tPA combination therapy could be a promising approach to improving the treatment of ischemic stroke.

167 Reversible VWF Inhibitor Lyses MCA Occlusion 6 Hours after Large Vessel Occlusion Stroke

INTRODUCTION: Acute ischemic stroke (AIS) is the leading cause of combined morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) represents the only approved pharmacological treatment for AIS but is limited to treating those within 4.5 hours of stroke onset because of the risk of intracranial hemorrhage. Moreover, it is ineffective in treating large vessel occlusion (LVO) stroke. For this population, endovascular mechanical thrombectomy (MT) effectively recanalizes the occlusion but is limited to highly-specialized hospitals, leaving the vast majority without timely acute treatment. METHODS: Utilizing a canine embolic middle cerebral artery occlusion (eMCAO) model of LVO stroke, we assessed DTRI-031 on vessel recanalization after 6 hours of LVO stroke by digital subtraction angiography (DSA). We also measured the effect of recanalization on infarct volume (efficacy) and hemorrhage (safety) using magnetic resonance imaging (MRI). Finally, we assessed the ability of DTRI-025, an oligonucleotide that binds DTRI-031 to reverse DTRI-031 activity. RESULTS: DTRI-031 administration after 6 hours of LVO stroke resulted in &gt;TICI 2A in 62.5% and &gt;TICI 2B in 50% of canines (n = 8). Negative control group demonstrated no revascularization (n = 7). Recanalization resulted in reduced infarct volume compared to negative control (p &lt; 0.05, unpaired t-test). None of the animals that received DTRI-031 had intracranial hemorrhage on MRI. Finally, DTRI-025 completely reversed the activity of DTRI-031 within 5 minutes of administration in both whole blood impedance aggregometry (WBA) and PFA-100. CONCLUSION: DTRI-031 effectively recanalizes LVO after 6 hours of stroke onset with reduced infarct volume and no incidence of hemorrhage. DTRI-025 rapidly reverses DTRI-031. This drug/reversal agent combination represents a robust yet safe approach to treat AIS.

Abstract 45: Vwf Inhibitor Lyses Middle Cerebral Artery Occlusion After 6 Hours Of Large Vessel Occlusion Stroke

Introduction: Acute ischemic stroke (AIS) is the leading cause of combined morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only FDA-approved drug to treat AIS, however, it is limited to treating patients within 4.5 hours of stroke onset because of the risk of intracranial hemorrhage. This limits rtPA administration to ~6% of patients. Moreover, it poorly lyses large vessel occlusion (LVO) stroke. Endovascular mechanical thrombectomy (MT) effectively recanalizes LVO but is limited to highly specialized hospitals, leaving the majority without acute therapy. Hypothesis: We hypothesize that targeted von Willebrand Factor (VWF) inhibition by DTRI-031 will recanalize arterial thrombosis in a canine model of LVO stroke, and DTRI-031 activity will be rapidly reversed by DTRI-025, which is specifically designed to inhibit DTRI-031. Methods: Utilizing a canine embolic middle cerebral artery occlusion (eMCAO) model of LVO stroke, we assessed DTRI-031 on vessel recanalization after 6 hours of LVO stroke by digital subtraction angiography (DSA). We also measured the effect of recanalization on infarct volume (efficacy) and hemorrhage (safety) using magnetic resonance imaging (MRI). Finally, we assessed the ability of DTRI-025, an oligonucleotide that binds DTRI-031 to reverse DTRI-031 activity. Results: DTRI-031 administration after 6 hours of LVO stroke resulted in ≥TICI 2A in 62.5% and ≥TICI 2B in 50% of canines (n=8). The negative control group demonstrated no revascularization (n=7). Recanalization resulted in reduced infarct volume compared to the negative control (p&lt;0.05, unpaired t-test). None of the animals that received DTRI-031 had an intracranial hemorrhage on MRI. Finally, DTRI-025 completely reversed the activity of DTRI-031 within 5 minutes of administration in both whole blood impedance aggregometry (WBA) and PFA-100. There was no difference in heart rate, blood pressure, or temperature among the 3 groups studied. Conclusion: DTRI-031 effectively recanalizes LVO after 6 hours of stroke onset with reduced infarct volume and no incidence of hemorrhage. DTRI-025 rapidly reverses DTRI-031. This drug/reversal agent combination represents a robust yet safe approach to treat AIS.