Search

Background: The mitochondrial unfolded protein response (UPR mt ) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPR mt may be a potential therapeutic target for ischemic stroke., Methods: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPR mt . We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro., Results: Inducing UPR mt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPR mt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPR mt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPR mt in vivo, which reduced infarction and improved neurological outcomes., Conclusions: These findings suggest that the UPR mt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPR mt mechanism may provide a new therapeutic avenue for ischemic stroke., Competing Interests: Disclosures None.

Background: Beyond neuronal injury, cell death pathways may also contribute to vascular injury after stroke. We examined protein networks linked to major cell death pathways and identified SLC22A17 (solute carrier family 22 member 17) as a novel mediator that regulates endothelial tight junctions after ischemia and inflammatory stress., Methods: Protein-protein interactions and brain enrichment analyses were performed using STRING, Cytoscape, and a human tissue-specific expression RNA-seq database. In vivo experiments were performed using mouse models of transient focal cerebral ischemia. Human stroke brain tissues were used to detect SLC22A17 by immunostaining. In vitro experiments were performed using human brain endothelial cultures subjected to inflammatory stress. Immunostaining and Western blot were used to assess responses in SLC22A17 and endothelial tight junctional proteins. Water content, dextran permeability, and electrical resistance assays were used to assess edema and blood-brain barrier (BBB) integrity. Gain and loss-of-function studies were performed using lentiviral overexpression of SLC22A17 or short interfering RNA against SLC22A17, respectively., Results: Protein-protein interaction analysis showed that core proteins from apoptosis, necroptosis, ferroptosis, and autophagy cell death pathways were closely linked. Among the 20 proteins identified in the network, the iron-handling solute carrier SLC22A17 emerged as the mediator enriched in the brain. After cerebral ischemia in vivo, endothelial expression of SLC22A17 increases in both human and mouse brains along with BBB leakage. In human brain endothelial cultures, short interfering RNA against SLC22A17 prevents TNF-α (tumor necrosis factor alpha)-induced ferroptosis and downregulation in tight junction proteins and disruption in transcellular permeability. Notably, SLC22A17 could repress the transcription of tight junctional genes. Finally, short interfering RNA against SLC22A17 ameliorates BBB leakage in a mouse model of focal cerebral ischemia., Conclusions: Using a combination of cell culture, human stroke samples, and mouse models, our data suggest that SLC22A17 may play a role in the control of BBB function after cerebral ischemia. These findings may offer a novel mechanism and target for ameliorating BBB injury and edema after stroke., Competing Interests: Disclosures Dr Wainger receives research funding from argenx and is a consultant for QurAlis Corporation. The other authors report no conflicts.

Aims: With the progress of thrombectomy technology, the vascular recanalization rate of patients with stroke has been continuously improved, but the proportion of futile recanalization (FR) is still quite a few. The long-term prognosis and survival of patients with FR and its influencing factors remain unclear., Methods: Consecutive patients who received endovascular treatment (EVT) for ischemic stroke were enrolled between 2013 and 2021 from a single-center prospectively registry study. We evaluated the long-term outcome of these patients by Kaplan-Meier survival analysis, and the multivariable logistic regression curve was performed to analyze influencing factors., Results: Among 458 patients with FR, 56.4% of patients survived at 1 year, and 50.4% at 2 years. In the multivariate regression analysis, age, premorbid modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), posterior circulation infarct, general anesthesia, symptomatic intracerebral hemorrhage (sICH), and decompressive craniectomy were found to be related to unfavorable outcomes in long-term. Age, premorbid mRS, NIHSS, general anesthesia, and sICH were predictors of long-term mortality., Conclusions: Futile recanalization accounts for a large proportion of stroke patients after thrombectomy. This study on the long-term prognosis of such patients is beneficial to the formulation of treatment plans and the prediction of therapeutic effects., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Rapid and selective therapeutic hypothermia is a promising neuroprotective method for acute ischemic stroke. A recent study developed a simple but efficient technique of transnasal cooling, in which air at ambient temperature was passed through standard nasal cannula to induce evaporative cooling of the brain. Selective brain temperature decrease was achieved within 25 minutes in piglets. It is a major step forward to initiate early brain cooling. However, it is still necessary to devise a more comprehensive strategy to enhance the benefits of selective brain cooling in the era of effective reperfusion., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Ischemic stroke (IS) is a cerebrovascular disease with high incidence and mortality. White matter repair plays an important role in the long-term recovery of neurological function after cerebral ischemia. Neuroprotective microglial responses can promote white matter repair and protect ischemic brain tissue., Aims: The aim of this study was to investigate whether hypoxic postconditioning (HPC) can promote white matter repair after IS, and the role and mechanism of microglial polarization in white matter repair after HPC treatment., Materials & Methods: Adult male C57/BL6 mice were randomly divided into three groups: Sham group (Sham), MCAO group (MCAO), and hypoxic postconditioning group (HPC). HPC group were subjected to 45 min of transient middle cerebral artery occlusion (MCAO) immediately followed by 40 min of HPC., Results: The results showed that HPC reduced the proinflammatory level of immune cells. Furthermore, HPC promoted the transformation of microglia to anti-inflammatory phenotype on the third day after the procedure. HPC promoted the proliferation of oligodendrocyte progenitors and increased the expression of myelination-related proteins on the 14th day. On the 28th day, HPC increased the expression of mature oligodendrocytes, which enhanced myelination. At the same time, the motor neurological function of mice was restored., Discussion: During the acute phase of cerebral ischemia, the function of proinflammatory immune cells was enhanced, long-term white matter damage was aggravated, and motor sensory function was decreased., Conclusion: HPC promotes protective microglial responses and white matter repair after MCAO, which may be related to the proliferation and differentiation of oligodendrocytes., (© 2023 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background: Ischemic stroke is a major cause of disability and death worldwide. A narrow therapeutic window profoundly constrained the utilization of alteplase., Objectives: To investigate therapeutic effects and safety of intravenous recombinant human prourokinase (rhPro-UK) in patients with acute ischemic stroke (AIS) in the 4.5-6 h therapeutic time windows., Methods: We conducted a phase IIa, randomized, and open-label multicenter clinical trial. Between 4.5 and 6 h after the onset of AIS, patients were randomly administrated to receive intravenous rhPro-UK at a 50 mg or 35 mg dose. The primary endpoint was excellent functional outcome defined as modified Rankin scale (mRS) score of 1 or less at 90 days. The secondary outcome was the treatment response, which was based on an at least 4-point improvement from baseline National Institutes of Health stroke scale (NIHSS) score at 24 h after drug administration. Safety endpoints included death, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events., Results: We enrolled 80 patients in the 4.5-6 h therapeutic time windows at 17 medical centers in China from December 2016 to November 2017. A total of 39 patients were treated with 50 mg rhPro-UK, and 39 were treated with 35 mg rhPro-UK. Compared with the baseline, the NIHSS score at 24 h and days 7, 14, 30, and 90 was decreased significantly among patients treated with either rhPro-UK 50 mg or 35 mg. The mean reduction in the NIHSS from baseline to 90 days after the onset was 3.56 and 5.79 in the rhPro-UK 50 mg group and the rhPro-UK 35 mg group, respectively. The rates of functional independence at 90 days of rhPro-UK 50 mg and 35 mg were 61.54% and 69.23%, respectively (P = 0.475), and the proportion of patients with functional response to treatment at 24 h were 28.21% and 33.33% (P = 0.624). No sICH occurred in the two groups, and death occurred in only one patient in the rhPro-UK 50 mg group. There was no significant difference in mortality at 90 days and the rate of other serious adverse events between two groups., Conclusion: In the 4.5-6 h time window, more than 60% of patients at either dose of rhPro-UK (50 mg or 35 mg) achieved functional independence at 90 days without increased mortality and sICH risk. Thus, intravenous rhPro-UK was effective and safe for patients with AIS within 4.5-6 h after stroke onset. While no significant differences were identified between different dosages of rhPro-UK regarding clinical outcomes, it is a logical step to further test the safety and efficacy of the low dose of rhPro-UK in a well-powered phase III study., Trial Registration: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: 6 June 2018., (© 2023. The Author(s).)

Vascular cognitive impairment (VCI) due to chronic cerebral hypoperfusion (CCH), is the second leading cause of dementia. Although synaptic impairment plays a critical role in VCI, its exact mechanism remains unknown. Our previous research revealed that remote ischemic conditioning (RIC) could alleviate cognitive decline resulting from CCH, however, its effects on synaptic impairment remain unclear. In this study, we confirmed that RIC alleviated both cognitive decline and its associated synaptic dysfunction caused by CCH. RNA sequencing revealed that CCH increased in miR-218a-5p expression, which was decreased by RIC. Elevated miR-218a-5p levels limited the benefits of RIC, however, inhibiting miR-218a-5p in hippocampal CA1 neurons rescued synaptic dysfunction. Additionally, we found that SHANK2 is a downstream target of miR-218a-5p, and inhibiting SHANK2 expression reduced the alleviation caused by hypoxic conditioning in synaptic impairment in vitro. In conclusion, our results suggested that RIC alleviated synaptic impairment via the miR-218a-5p/SHANK2 pathway, which could be a potential biomarker or therapeutic target for cognitive impairment caused by CCH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Zinc plays important roles in both physiological and pathological processes in the brain. Accumulation of free zinc in ischemic tissue is recognized to contribute to blood-brain barrier (BBB) disruption following cerebral ischemia, but little is known either about the source of free zinc in microvessels or the mechanism by which free zinc mediates ischemia-induced BBB damage. We utilized cellular and animal models of ischemic stroke to determine the source of high levels of free zinc and the mechanism of free zinc-mediated BBB damage after ischemia. We report that cerebral ischemia elevated the level of extracellular fluid (ECF-Zn) of ischemic brain, leading to exacerbated BBB damage in a rat stroke model. Specifically suppressing zinc release from neurons, utilizing neuronal-specific zinc transporter 3 (ZnT3) knockout mice, markedly reduced ECF-Zn and BBB permeability after ischemia. Intriguingly, the activity of zinc-dependent metalloproteinase-2 (MMP-2) was modulated by ECF-Zn levels. Elevated ECF-Zn during ischemia directly bound to MMP-2 in extracellular fluid, increased its zinc content and augmented MMP-2 activity, leading to the degradation of tight junction protein in cerebral microvessels and BBB disruption. These findings suggest the role of neuronal ZnT3 in modulating ischemia-induced BBB disruption and reveal a novel mechanism of MMP-2 activation in BBB disruption after stroke, demonstrating ZnT3 as an effective target for stroke treatment.

Neuron-specific conventional protein kinase C (cPKC)γ mediates cerebral hypoxic preconditioning (HPC). In parallel, autophagy plays a prosurvival role in ischemic preconditioning (IPC) against ischemic stroke. However, the effect of cPKCγ on autophagy in IPC still remains to be addressed. In this study, adult and postnatal 1-day-old C57BL/6 J wild-type (cPKCγ +/+ ) and knockout (cPKCγ -/- ) mice were used to establish in vivo and in vitro IPC models. The results showed that IPC pretreatment alleviated neuronal damage caused by lethal ischemia, which could be suppressed by autophagy inhibitor 3-MA or bafilomycin A1. Meanwhile, cPKCγ knockout blocked IPC-induced neuroprotection, accompanied by significant increase of LC3-I to LC3-II conversion and Beclin 1 protein level, and a significant decrease in p62 protein level. Immunofluorescent staining results showed a decrease of LC3 puncta numbers in IPC-treated cPKCγ +/+ neurons with fatal ischemia, which was reversed in cPKCγ -/- neurons. In addition, cPKCγ-modulated phosphorylation of mTOR at Ser 2448 and ULK1 at Ser 555, rather than p-Thr-172 AMPK, was detected in IPC-pretreated neurons upon lethal ischemic exposure. The present data demonstrated that cPKCγ-modulated autophagy via the mTOR-ULK1 pathway likely modulated IPC-induced neuroprotection., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The proper imaging modality for use in the selection of patients for endovascular thrombectomy (EVT) presenting in the late window remains controversial, despite current guidelines advocating the use of advanced imaging in this population. We sought to understand if clinicians with different specialty training differ in their approach to patient selection for EVT in the late time window., Methods: We conducted an international survey of stroke and neurointerventional clinicians between January and May 2022 with questions focusing on imaging and treatment decisions of large vessel occlusion (LVO) patients presenting in the late window. Interventional neurologists, interventional neuroradiologists, and endovascular neurosurgeons were defined as interventionists whereas all other specialties were defined as non-interventionists. The non-interventionist group was defined by all other specialties of the respondents: stroke neurologist, neuroradiologist, emergency medicine physician, trainee (fellows and residents) and others., Results: Of 3000 invited to participate, 1506 (1027 non-interventionists, 478 interventionists, 1 declined to specify) physicians completed the study. Interventionist respondents were more likely to proceed directly to EVT (39.5% vs. 19.5%; p < 0.0001) compared to non-interventionist respondents in patients with favorable ASPECTS (Alberta Stroke Program Early CT Score). Despite no difference in access to advanced imaging, interventionists were more likely to prefer CT/CTA alone (34.8% vs. 21.0%) and less likely to prefer CT/CTA/CTP (39.1% vs. 52.4%) for patient selection (p < 0.0001). When faced with uncertainty, non-interventionists were more likely to follow clinical guidelines (45.1% vs. 30.2%) while interventionists were more likely to follow their assessment of evidence (38.7% vs. 27.0%) (p < 0.0001)., Conclusion: Interventionists were less likely to use advanced imaging techniques in selecting LVO patients presenting in the late window and more likely to base their decisions on their assessment of evidence rather than published guidelines. These results reflect gaps between interventionists and non-interventionists reliance on clinical guidelines, the limits of available evidence, and clinician belief in the utility of advanced imaging., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Experimental studies have demonstrated the neuroprotection of ischemic postconditioning (IPostC) in acute ischemic stroke by attenuating ischemia-reperfusion injury. This study aimed to investigate the safety and tolerability of direct IPostC in both a dog model and patients with acute ischemic stroke treated with thrombectomy., Methods: The study involved 2 parts. First, IPostC was induced by repeated balloon inflation and deflation in dogs, where a low-pressure balloon was navigated to the anterior spinal artery, and 4 cycles of 5-minute ischemia followed by 5-minute reperfusion were performed. Vascular injuries were assessed using angiography and vascular tissue specimens. Then, a 3+3 dose-escalation trial was conducted in patients with acute ischemic stroke following successful thrombectomy recanalization. Patients received direct IPostC with ischemia and reperfusion durations in progressive increments of 0, 1, 2, 3, 4, and 5 minutes ×4 cycles. Major adverse responses were defined as vessel perforation, rupture, dissection, reocclusion, severe vasospasm, thrombotic events, and rupture of the balloon., Results: IPostC was investigated in 4 dogs. No vessel perforation or rupture, dissection, or vasospasm was observed under the angiography. Only 1 vessel experienced mild injury between the intima and the internal elastic membrane detected on a histopathologic slide. Then, 18 patients were recruited. The duration of IPostC was progressively escalated with no major response happened. No patient experienced agitation, discomfort, or other tolerability issues. Five patients (27.8%) experienced any intracranial hemorrhage after thrombectomy, and 1 (5.6%) was symptomatic. At 3-month follow-up, no patient died, and 9 patients (50%) achieved functional independence., Conclusions: Direct IPostC inducing by 4 cycles of 5-minute ischemia followed by 5-minute reperfusion is safe, feasible, and tolerable in patients with acute ischemic stroke treated with thrombectomy. Further investigations are needed to determine the safety and preliminary efficacy of direct IPostC., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT05153655., Competing Interests: Disclosures Dr Hess reports compensation from Athersys, Inc, for other services and a patent issued for use of multipotent adult progenitor cells in neurological diseases licensed to Athersys, Inc. The other authors report no conflicts.

Although hypoxic postconditioning (HPC) has a protective effect on ischemic stroke, its effect on angiogenesis after ischemic stroke is still unclear. This study was designed to investigate the effects of HPC on angiogenesis after ischemic stroke and to preliminarily study the mechanism involved. Oxygen-glucose deprivation (OGD)-intervened bEnd.3 (mouse brain-derived Endothelial cell. 3) was used to simulate cerebral ischemia. Cell counting kit-8 (CCK-8), Cell BrdU proliferation, wound healing, Transwell and tube formation assays were used to evaluate the effect of HPC on the cell viability, proliferation, migration (horizontal and vertical migration), morphogenesis and tube formation of bEnd.3. A middle cerebral artery occlusion (MCAO) model was made in C57 mice to simulate focal cerebral ischemia. Rod rotation test, corner test, modified neurological severity score (mNSS), and balance beam walking test were used to evaluate the effect of HPC on the neurological impairment of mice. Immunofluorescence staining was used to evaluate the effect of HPC on angiogenesis in mice. The angiogenesis-related proteins were evaluated and quantified using western blot. Results showed that HPC significantly promoted proliferation, migration and tube formation of bEnd.3. HPC significantly reversed the neurological deficit of MCAO mice. Moreover, HPC significantly promoted angiogenesis in the peri-infarct area, and angiogenesis was found to be positively correlated with the improvement of neurological impairment. The HPC mice showed higher PLCλ and ALK5 than did MCAO. We conclude that HPC improves the neurological deficit caused by focal cerebral ischemia by promoting angiogenesis. Furthermore, the effect of HPC on improving angiogenesis may be related to PLCλ and ALK5., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Whether preceding transient ischemic attack (TIA) can provide neuroprotective benefits in subsequent acute ischemic stroke (AIS) caused by large vessel occlusion remains unclarified. This study aimed to investigate the association between preceding TIA and functional outcomes in AIS patients with endovascular therapy (EVT). Eligible patients were divided into TIA and non-TIA groups according to whether they experienced TIA within 96 hours prior to stroke. Two groups were balanced using propensity score matching (PSM) analysis at a 1:3 ratio. Onset stroke severity and 3-month functional independence were evaluated. A total of 887 patients were included. After PSM, 73 patients with and 217 patients without preceding TIA were well matched. Onset stroke severity was not different between the groups (p > 0.05). However, the TIA group had a lower systemic immune-inflammation index (SII) (median, 1091 versus 1358, p < 0.05). Preceding TIA was significantly associated with 3-month functional independence (adjusted odds ratio, 2.852; 95% confidence interval [CI], 1.481-5.495; adjusted p < 0.01). The effects of preceding TIA on functional independence were partially mediated by SII (average causal mediation effects 0.02; 95% CI, 0.001-0.06, p < 0.05). In AIS patients treated by EVT, preceding TIA within 96 hours was associated with three-month functional independence but not with reduced onset stroke severity.

Background: To determine whether intra-arterial thrombolysis (IAT) within 16 hours after the onset of symptoms is feasible and associated with better visual outcomes in patients with acute retinal ischemia (ARI)., Methods: The retrospective cohort study was performed from January 2014 to December 2021 in the Xuanwu Hospital of Capital Medical University. Patients with ARI who initially presented visual acuity of 20/100 or worse were screened in the study. Visual end points were evaluated at one week and at final visit after treatment. Serious adverse events were recorded during operation and within 1 week after IAT treatment., Results: The amount of clinically significant visual improvement (≥0.3 logarithm of the minimum angle of resolution) in the IAT group was significantly higher than that in the conservative treatment group at one week after the treatment (47.8% vs 16.7%; P = 0.014) and at final visit (52.2% vs 20%; P = 0.014). After controlling confounding factors, ARI treatment was the only factor significantly associated with the amount of clinically significant visual improvement (OR, 4.364; 95 CI, 1.298-14.667; P = 0.017). A patient (4.3%) experienced retinal hemorrhage without symptom within 1 week after IAT treatment. No patients experienced new symptomatic cerebral infarction, intracranial hemorrhage, TIA, artery dissection, vascular perforation, and distal embolization during operation and within 1 week after IAT treatment., Conclusions: IAT may be associated with better visual improvement within 16 hours after the onset of symptoms. Besides, IAT is feasible and associated with a low risk of periprocedural complications for ARI. This study will aid in feasibility testing and sample size calculations in advance of future, fully-powered efficacy studies for ARI., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by North American Neuro-Ophthalmology Society.)

Importance: Preclinical and clinical studies have suggested the neuroprotective effect of Panax notoginseng saponins (Xuesaitong soft capsules). However, robust evidence in patients with ischemic stroke is lacking., Objective: To assess the efficacy and safety of Xuesaitong soft capsules in patients with ischemic stroke., Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 67 tertiary health centers in China from July 1, 2018, to June 30, 2020. Included patients were aged 18 to 75 years with a diagnosis of ischemic stroke and a National Institutes of Health Stroke Scale score between 4 and 15., Interventions: Eligible patients were randomly assigned within 14 days after symptom onset to receive either treatment with Xuesaitong soft capsules (120 mg orally twice daily) or placebo (120 mg orally twice daily) for 3 months., Main Outcomes and Measures: The primary outcome was functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2., Results: Among 3072 eligible patients with ischemic stroke who were randomized, 2966 (96.5%) were included in the modified intention-to-treat cohort (median [IQR] age, 62 [55-68] years; 1982 male [66.8%]). The number of patients who achieved functional independence at 3 months was 1328 (89.3%) in the Xuesaitong group and 1218 (82.4%) in the control group (odds ratio, 1.95; 95% CI, 1.56-2.44; P < .001). In the safety cohort, serious adverse events occurred in 15 of 1488 patients (1.0%) in the Xuesaitong group and 16 of 1482 (1.1%) in the control group (P = .85)., Conclusions and Relevance: In this randomized clinical trial, Xuesaitong soft capsules significantly increased the likelihood of functional independence at 3 months in patients with ischemic stroke, indicating that this may be a safe and effective alternative therapy to improve prognosis in this population., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800016363.

Objectives: To investigate the relationship between the initiation time of anticoagulation after endovascular treatment (EVT) and the outcomes in atrial fibrillation (AF)-related acute ischemic stroke (AIS) patients., Methods: In this prospective registry study, from March 2013 to June 2022, patients with anterior circulation territories AF-related AIS who underwent EVT within 24 h were included. The primary outcome was favorable [modified Rankin Scale (mRS) 0-1) at ninety days and the secondary outcome was hemorrhage events after anticoagulants. Factors affecting the outcomes were pooled into multivariate regression and ROC curve analysis., Results: Of 234 eligible patients, there were 63 (26.9%) patients achieved a favorable outcome. The symptomatic intracranial hemorrhage (sICH), ICH, and systemic hemorrhage events after anticoagulants occurred in 8 (3.4%), 28 (12.0%), and 39 (16.7%) patients, severally. A longer EVT to anticoagulation time (p = 0.033) was associated with an unfavorable outcome (mRS 3-6). An earlier EVT to anticoagulation time was the independent risk factor of sICH (p = 0.043), ICH (p = 0.005), and systemic hemorrhage (p = 0.005). There was no significant difference in recurrent AIS/ transient ischemic attack (TIA) or mortality among patients who started anticoagulation at ≤ 4 days, ≥ 15 days, or 4 to 15 days. The optimum cut-off for initiating anticoagulants to predict a favorable outcome and hemorrhage events was 4.5 days and 3.5 days after EVT, respectively., Conclusions: In AF-related AIS, the time of EVT to anticoagulation is an independent factor of the functional outcome and hemorrhage events after anticoagulation. The optimal initiate time of anticoagulant after EVT is 4.5 days., Clinicaltrialregister: NCT03754738., (© 2023. The Author(s).)

Aims: Remote ischemic pre-conditioning (RIPC) protects against ischemia/reperfusion (I/R) injury. However, the mechanisms underlying this protection remain unclear. In the present study, we investigated the role of Janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway and cell cycle arrest, and their relationship with neuronal apoptosis following RIPC., Methods: A rat cerebral I/R injury model was induced by middle cerebral artery occlusion (MCAO), and AG490 was used to investigate the mechanisms of RIPC. p-JAK2-, p-STAT3-, cyclin D1-, and cyclin-dependent kinase 6 (CDK6) expression was assessed by Western blotting and immunofluorescence staining., Results: RIPC reduced the infarct volume, improved neurological function, and increased neuronal survival. Furthermore, p-JAK2 and p-STAT3 were detected during the initial phase of reperfusion; the expression levels were significantly increased at 3 and 24 h after reperfusion and were suppressed by RIPC. Additionally, the MCAO-induced upregulation of the cell cycle regulators cyclin D1 and CDK6 was ameliorated by RIPC. Meanwhile, cyclin D1 and CDK6 were colocalized with p-STAT3 in the ischemic brain., Conclusion: RIPC ameliorates the induction of the JAK2/STAT3 pathway and cell cycle regulators cyclin D1 and CDK6 by MCAO, and this net inhibition of cell cycle re-entry by RIPC is associated with downregulation of STAT3 phosphorylation., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aims: To investigate the predicted factors influencing the outcomes in acute ischemic stroke (AIS) patients who received tirofiban after endovascular treatment (EVT) and the optimal administration of tirofiban., Methods: In this retrospective study, AIS patients who received EVT followed by tirofiban between January 2017 and October 2021 were enrolled. The dose and duration of tirofiban were adjusted by trained clinicians according to the patient's clinical status. A reduction of at least four points on the National Institutes of Health Stroke Scale (NIHSS) after tirofiban compared with that before tirofiban was defined as an effective response. A modified ranking scale (mRS) of 0-2 was defined as a favorable outcome at a 90-day follow-up., Results: A total of 260 consecutive patients were enrolled, and 36.5% of patients achieved a favorable outcome. The modified thrombolysis in cerebral infarction (mTICI) 2b-3 occurred in 93.5% of patients. Symptomatic intracerebral hemorrhage (sICH) occurred in 6.2% of patients, and the mortality at 90-day follow-up was 16.9%. Duration of tirofiban >24 h (adjusted OR: 2.545; 95% CI: 1.008-6.423; p = 0.048) and effective response to tirofiban (adjusted OR: 25.562; 95% CI: 9.794-66.715; p < 0.001) were related to the favorable outcome (mRS 0-2). Higher NIHSS (adjusted OR: 0.855; 95% CI: 0.809-0.904; p < 0.001) and glucose level on admission (adjusted OR: 0.843; 95% CI: 0.731-0.971; p = 0.018) were predictive for the unfavorable outcome (mRS 3-6)., Conclusions: An effective response to tirofiban is an independent factor in predicting the long-term efficacy outcome, and extending the duration of tirofiban is beneficial for neurological improvement., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Diabetes mellitus (DM) is a major risk factor for stroke and exacerbates white-matter damage in focal cerebral ischemia. Our previous study showed that the sigma-1 receptor agonist PRE084 ameliorates bilateral common-carotid-artery occlusion-induced brain damage in mice. However, whether this protective effect can extend to white matter remains unclear. In this study, C57BL/6 mice were treated with high-fat diets (HFDs) combined with streptozotocin (STZ) injection to mimic type 2 diabetes mellitus (T2DM). Focal cerebral ischemia in T2DM mice was established via injection of the vasoconstrictor peptide endothelin-1 (ET-1) into the hippocampus. Three different treatment plans were used in this study. In one plan, 1 mg/kg of PRE084 (intraperitoneally) was administered for 7 d before ET-1 injection; the mice were sacrificed 24 h after ET-1 injection. In another plan, PRE084 treatment was initiated 24 h after ET-1 injection and lasted for 7 d. In the third plan, PRE084 treatment was initiated 24 h after ET-1 injection and lasted for 21 d. The Y-maze, novel object recognition, and passive avoidance tests were used to assess neurobehavioral outcomes. We found no cognitive dysfunction or white-matter damage 24 h after ET-1 injection. However, 7 and 21 d after ET-1 injection, the mice showed significant cognitive impairment and white-matter damage. Only PRE084 treatment for 21 d could improve this white-matter injury; increase axon and myelin density; decrease demyelination; and increase the expressions of myelin regulator 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNpase) and myelin oligodendrocyte protein (MOG) (which was expressed by mature oligodendrocytes), the number of nerve/glial-antigen 2 (NG2)-positive cells, and the expression of platelet-derived growth factor receptor-alpha (PDGFRα), all of which were expressed by oligodendrocyte progenitor cells in mice with diabetes and focal cerebral ischemia. These results indicate that maybe there was more severe white-matter damage in the focal cerebral ischemia of the diabetic mice than in the mice with normal blood glucose levels. Long-term sigma-1 receptor activation may promote oligodendrogenesis and white-matter functional recovery in patients with stroke and with diabetes.

Background: At least one-third of Alzheimer's disease (AD) patients have cerebrovascular abnormalities, micro- and macro-infarctions, and ischemic white matter alterations. Stroke prognosis impacts AD development due to vascular disease. Hyperglycemia can readily produce vascular lesions and atherosclerosis, increasing the risk of cerebral ischemia. Our previous research has demonstrated that protein O-GlcNAcylation, a dynamic and reversible post-translational modification, provides protection against ischemic stroke. However, the role of O-GlcNAcylation in the exacerbation of cerebral ischemia injury due to hyperglycemia remains to be elucidated., Objective: In this study, we explored the role and underlying mechanism of protein O-GlcNAcylation in the exacerbation of cerebral ischemia injury caused by hyperglycemia., Methods: High glucose-cultured brain microvascular endothelial (bEnd3) cells were injured by oxygen-glucose deprivation. Cell viability was used as the assay result. Stroke outcomes and hemorrhagic transformation incidence were assessed in mice after middle cerebral artery occlusion under high glucose and streptozotocin-induced hyperglycemic conditions. Western blot estimated that O-GlcNAcylation influenced apoptosis levels in vitro and in vivo., Results: In in vitro analyses showed that Thiamet-G induces upregulation of protein O-GlcNAcylation, which attenuates oxygen-glucose deprivation/R-induce injury in bEnd3 cells cultured under normal glucose conditions, while aggravated it under high glucose conditions. In in vivo analyses, Thiamet-G exacerbated cerebral ischemic injury and induced hemorrhagic transformation, accompanied by increased apoptosis. While blocking protein O-GlcNAcylation with 6-diazo-5-oxo-L-norleucine alleviated cerebral injury of ischemic stroke in different hyperglycemic mice., Conclusion: Overall, our study highlights the crucial role of O-GlcNAcylation in exacerbating cerebral ischemia injury under conditions of hyperglycemia. O-GlcNAcylation could potentially serve as a therapeutic target for ischemic stroke associated with AD.

Aims: This study aimed to investigate the effects of mild selective brain hypothermia on aged female ischemic mice., Methods: A distal middle cerebral artery occlusion (dMCAO) model was established in aged female mice, who were then subjected to mild selective brain hypothermia immediately after the dMCAO procedure. Neurological behavioral examinations were conducted prior to and up to 35 days post-ischemia. Infarct volume, brain atrophy, pro-inflammation, and anti-inflammation microglia/macrophages phenotype and white matter injury were evaluated by immunofluorescence staining. Correlations between neurological behaviors and histological parameters were evaluated by Pearson product linear regression analysis., Results: Sensorimotor and cognitive function tests confirmed the protective effect of mild selective brain hypothermia in elderly female ischemic mice. In addition, hypothermia decreased the infarct volume and brain atrophy induced by focal cerebral ischemia. Furthermore, hypothermia alleviated ischemia-induced short-term and long-term white matter injury, which was correlated with behavioral deficits. Finally, hypothermia suppressed the harmful immunological response by promoting the transformation of pro-inflammatory microglia/macrophages to anti-inflammatory phenotype. This polarization was negatively correlated with neuronal loss and white matter injury., Conclusion: Mild selective brain hypothermia promoted long-term functional recovery by alleviating white matter damage in an aged female mouse model of ischemia., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: This study aimed to explore the effect of different administration routes of a low dose of tirofiban on acute ischemic stroke (AIS) patients with successful recanalization after endovascular treatment (EVT)., Methods: This is a cohort study that retrospectively analyzed data of patients with AIS who underwent EVT and achieved successful recanalization from a prospective registry. Eligible patients were divided into three groups according to their use of tirofiban. Propensity score matching (PSM) was used to balance baseline bias. Safety outcomes included any intracranial hemorrhage (ICH) and symptomatic ICH (sICH). Efficacy outcomes included arterial reocclusion, in-hospital mortality, 3-month mortality, and 3-month functional outcomes., Results: We included 821 patients with 306 in the no tirofiban group, 202 in the IA + IV tirofiban group, and 313 in the IV tirofiban group. After PSM, each group included 101 patients with balanced baseline characteristics. There was no difference between the IV tirofiban group and the no tirofiban group in terms of safety and efficacy outcomes (all p > 0.05). Compared with no tirofiban, IA + IV tirofiban group did not increase ICH (30.7% vs. 37.6%, p > 0.05) and sICH (6.9% vs. 17.8%, p > 0.05) whereas reduced 3-month mortality (14.3% vs. 28.7%, p < 0.05) and improved 3-month modified Rankin Scale (median 3 vs. 4, p < 0.05)., Conclusions: A low dose of tirofiban, regardless of their administration routes, was safe for AIS patients who achieved successful recanalization with EVT, whereas only IA + IV tirofiban improved clinical outcomes., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Recombinant human prourokinase (rhPro-UK) is a novel thrombolytic that has been approved to treat patients with acute myocardial infarction. However, the safety and efficacy of intravenous rhPro-UK in patients with acute ischemic stroke (AIS) has not been well established. We aimed to investigate the safety and preliminary efficacy of rhPro-UK in patients with AIS in a multi-center phase IIa trial setting. One hundred nineteen patients within 4.5 h of AIS onset were enrolled in this randomized, open-label, 23-center phase IIa clinical trial. Patients were randomly assigned to 35 mg (n = 40) or 50 mg (n = 39) intravenous rhPro-UK or 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA; n = 40). The primary endpoint was functional independence defined as a modified Rankin scale (mRS) score of 0 or 1 at 90 days. The secondary outcome was early neurological improvement defined as a reduction of ≥ 4 points on the National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 h after drug administration. Safety endpoints included death due to any cause, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events (SAEs). The proportion of patients with an mRS score of ≤ 1 at 90 days did not differ significantly among three groups (35 mg rhPro-UK: 55.56% vs. 50 mg rhPro-UK: 57.89% vs. vs. r-tPA: 52.63%; P = 0.92). The rates of treatment response, referring to early neurological improvement, were similar among these three groups (36.11% vs. 31.58% vs. 28.95%, respectively; P = 0.85). There was no difference in mortality at 90 days or in the rate of other SAEs among the three groups. One patient in the 50 mg rhPro-UK group suffered sICH. While neither the primary efficacy outcomes nor safety profile differed significantly among the low, high rhPro-UK and control groups, it is a logical step to further test the low-dose rhPro-UK group versus the control group in a well-powered phase III study.Trial Registration: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: June 6 2018., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To investigate the association between time-of-day of stroke onset and functional outcome in patients with acute ischemic stroke(AIS) treated with endovascular thrombectomy(EVT). AIS patients treated with EVT between January 2013 and December 2018 were recruited and divided them into four 6-h interval groups according to the time-of-day of stroke onset. A total of 438 patients were enrolled, 3-month favorable outcome were achieved in 58.6%, 43.7%, 36.6%, and 30.5% of patients in the 00:00-06:00, 06:00-12:00, 12:00-18:00, and 18:00-24:00 groups, respectively (adjusted OR 0.61, 95% CI 0.40-0.93; p  = 0.020). Compared with the 18:00-24:00 interval, patients in the 00:00-06:00 interval (adjusted OR 4.01, 95%CI 1.02-15.80, p  = 0.047) and the 06:00-12:00 interval (adjusted OR 3.24, 95% CI 1.09-9.64, p  = 0.034) were more likely to achieve favorable outcome. The time-of-day of stroke onset was not associated with 3-month mortality (adjusted p = 0.829), symptomatic intracerebral hemorrhage (sICH, adjusted p  = 0.296), or early successful recanalization (adjusted p  = 0.074). In conclusion, in AIS patients treated with EVT, those onsets either between 00:00 and 06:00 or between 06:00 and 12:00 appeared to be associated with a higher proportion of favorable outcomes at 3 months, but the time-of-day at stroke onset was not associated with the incidence of sICH, rate of early successful recanalization, or 3-month mortality.

Background: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide, and it is associated with a high risk of recurrent stroke with currently recommended treatments. We aimed to evaluate the effect of chronic remote ischaemic conditioning on prevention of ischaemic events in patients with symptomatic ICAS., Methods: The RICA trial is a multicentre, randomised, double-blind, sham-controlled trial at 84 stroke centres in China. Patients aged 40-80 years with ischaemic stroke or transient ischaemic attack attributable to angiographically verified 50-99% stenosis of a major intracranial artery were randomly assigned (1:1), via an interactive web-based system by computer-generated randomisation code, to either remote ischaemic conditioning or sham remote ischaemic conditioning once daily for 12 months and voluntarily thereafter. All investigators and patients were masked to treatment allocation. The primary efficacy endpoint was the time to first occurrence of non-fatal or fatal ischaemic stroke, with survival analysed by the Kaplan-Meier method. Primary and safety analyses were done in the intention-to-treat population. The RICA trial is registered with ClinicalTrials.gov, number NCT02534545., Findings: Between Oct 28, 2015, and Feb 28, 2019, 3033 patients were enrolled and randomly assigned to either remote ischaemic conditioning (n=1517; intervention group) or sham remote ischaemic conditioning (n=1516; sham group). Median follow-up was 3·5 years (IQR 2·7-4·4). A non-fatal or fatal ischaemic stroke occurred in 257 (16·9%) patients in the intervention group compared with 288 (19·0%) patients in sham group. There was no difference in the survival distribution for time to first occurrence of non-fatal or fatal ischaemic stroke (hazard ratio 0·87, 95% CI 0·74-1·03; p=0·12). In the intervention group, 79 (5·2%) patients died from any cause, and in the sham group, 84 (5·5%) patients died from any cause (hazard ratio 0·93, 95% CI 0·68-1·27; p=0·65). No intervention-related serious adverse events were observed., Interpretation: No evidence was found for a difference between remote ischaemic conditioning and sham remote ischaemic conditioning in lowering the risk of ischaemic stroke in patients with symptomatic ICAS. The benefit of remote ischaemic conditioning might have been diluted by poor compliance. Future studies of remote ischaemic conditioning in this population should address challenges in patients' compliance and assess longer term treatment., Funding: Ministry of Science and Technology China, Beijing Municipal Education Commission, Beijing Municipal Finance Bureau., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests CH has received speaker fees from Novo Nordisk and Pfizer. HS has received speaker fees from AstraZeneca, Pzier, Amgen, Boehringer Ingelheim, Novartis, and Sanofi. WZ has received speaker fees from Tasly Pharma. RM has received grants from Ministry of Science and Technology of the People's Republic of China. MIC has received grants from National Institute of Health (CAPTIVA, U01 NS117450–01A1). MIC has received honoraria for lectures on intracranial stenosis at Taiwan Neurological Conference, Taipei, April 1, 2021 (virtual presentation) and Grand Rounds at Harvard University, Cornell University, Dignity Health, and Northwell Health. DCH is on the Scientific Advisosry Board of Athersys, Inc and has received royalty payments. DSL has served as CEC member. DJH has received consultant fees from Faraday Pharmaceuticals Inc. and Boehringer Ingelheim International GmbH; honoraria from Servier; and research funding from Astra Zeneca and Merck Sharp & Dohme Corp. XZ has received speaker fees from AstraZeneca and Bayer. GL has received speaker fees from Techpool, CSPC, and Boehringer Ingelheim. WY has participated in speakers bureaus and received speaker fees from Bayer, Sanofi, Novartis, Xian Janssen, and Amgen. XJ has received grants from Beijing Municipal Education Commission and Beijing Municipal Finance Bureau. XJ has received speaker fees from AstraZeneca, Medtronic, and Sanofi. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Acute cerebral ischemia is caused by an insufficient blood supply to brain tissue. Oxygen therapy, which is able to aid diffusion to reach the ischemic region, has been regarded as a possible treatment for cerebral ischemia. Recent animal and pilot clinical studies have reported that normobaric hyperoxia (NBO) showed neuroprotective effects if started soon after the onset of stroke. However, little is known about the role and mechanism of NBO treatment in astrocytes. Connexin43, one of the main gap junction proteins in astrocytes, is extremely sensitive to hypoxia and oxidative stress after cerebral ischemia., Aims: In the present study, we used sutures to develop an ischemia/reperfusion model in rats to mimic clinical recanalization and investigated the role of connexin43 in NBO-treated stroke rats, as well as the underlying mechanism of NBO therapy., Results: Normobaric hyperoxia treatment maintained the homeostasis of oxidoreductases: glutathione peroxidase 4 (GPX4) and NADPH oxidase 4 (two important oxidoreductases) and rescued the ischemia/reperfusion-induced downregulation of connexin43 protein in astrocytes. Furthermore, NBO treatment attenuated cerebral ischemia-induced cytochrome c release from mitochondria and was involved in neuroprotective effects by regulating the GPX4 and connexin43 pathway, using Ferrostatin-1 (an activator of GPX4) or Gap27 (an inhibitor of connexin43)., Conclusions: This study showed the neuroprotective effects of NBO treatment by reducing oxidative stress and maintaining the level of connexin43 in astrocytes, which could be used for the clinical treatment of ischemic stroke., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aims: To evaluate pulsatility index (PI) in patients with acute ischemic stroke (AIS) who underwent endovascular thrombectomy (EVT)., Methods: Patients were retrospectively recruited if their stroke were secondary to middle cerebral artery (MCA) occlusion and achieved full recanalization after EVT. Transcranial Doppler was performed within 24-hour post-EVT. The primary outcome was correlation between the MCA-PI on the affected side and 3-month functional outcome, with modified Rankin scale (mRS) ≥5 indicated extremely poor functional outcomes., Results: Totally, 170 patients were included. High MCA-PI was positively related to the 3-month mRS score (r = 0.288, p < 0.001). The highest quartile of the MCA-PI was associated with a high incidence of extremely poor functional outcomes (adjusted OR, 13.33; 95% CI, 2.65-67.17; adjusted p = 0.002) after adjusting for confounding factors. The predictive capacity of the MCA-PI for extremely poor functional outcomes was good (area under the curve, 0.755; 95% CI, 0.655-0.854; p < 0.001), and its cutoff value for predicting extremely poor outcomes was 1.04, with a sensitivity of 65.6% and specificity of 78.3%., Conclusion: The MCA-PI on the affected side is a prognostic biomarker in patients who have undergone stroke thrombectomy. An elevated MCA-PI may be prognostically valuable for predicting extremely poor functional outcomes., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Over decades of research into the treatment of stroke, nearly all attempts to translate experimental treatments from discovery in cells and rodents to use in humans have failed. The prevailing belief is that it might be necessary to pretest pharmacological neuroprotection in higher-order brains, especially those of nonhuman primates (NHPs). Over the past few years, chemical thrombolysis and mechanical thrombectomy have been established as the standard of care for ischemic stroke in patients. The spotlight is now shifting towards emphasizing both focal ischemia and subsequent reperfusion in developing a clinically relevant stroke model in NHPs. This protocol describes an embolic model of middle cerebral artery occlusion in adult rhesus monkeys. An autologous clot is combined with a microcatheter or microwire through endovascular procedures, and reperfusion is achieved through local intra-artery thrombolysis with tissue plasminogen activator. These NHP models formed relatively stable infarct sizes, delivered predictable reperfusion and survival outcomes, and recapitulated key characteristics of patients with ischemic stroke as observed on MRI images and behavioral assays. Importantly, treated animals could survive 30 d after the surgery for post-stroke neurologic deficit analyses. Thus far, this model has been used in several translational studies. Here we describe in detail the teamwork necessary for developing stroke models of NHPs, including the preoperation preparations, endovascular surgery, postoperation management and histopathological analysis. The model can be established by the following procedures over a 45-d period, including preparation steps (14 d), endovascular operation (1 d) and evaluation steps (30 d)., (© 2022. Springer Nature Limited.)

Background and Objectives: To investigate the safety and efficacy of normobaric hyperoxia (NBO) combined with endovascular treatment (EVT) in patients with acute ischemic stroke (AIS)., Methods: In this single-center, proof-of-concept, assessor-blinded, randomized, controlled pilot study, patients with AIS in the acute anterior circulation with large vessel occlusion who had an indication for EVT were randomly assigned to the EVT group or the NBO + EVT group. The NBO + EVT group was given 100% oxygen through a face mask initiated before vascular recanalization (10L/min for 4 hours), while the EVT group was given room air. The primary endpoint was infarct volume measured by MRI within 24-48 hours after randomization., Results: A total of 231 patients were screened, and 86 patients were randomized into a ratio of 1:1 (EVT group, n = 43; NBO + EVT group, n = 43). The median infarction volume of the NBO + EVT group at 24-48 hours after randomization was significantly smaller than that of the EVT group (median 20.1 vs 37.7 mL, p < 0.01). The median mRS score at 90 days was 2 for the NBO + EVT group when compared with 3 for the EVT group (adjusted value 1.8, 95% CI 1.3-4.2; p = 0.038). Compared with the EVT group, the NBO + EVT group had a lower incidence of symptomatic intracranial hemorrhagic (7% vs 12%), mortality (9% vs 16%), and adverse events (33% vs 42%); however, such a difference was not statistically significant., Discussion: NBO in combination with EVT seems to be a safe and feasible treatment strategy that could significantly reduce infarct volume, improve short-term neurobehavioral test score, and enhance clinical outcomes at 90 days when compared with EVT alone in patients with AIS. These observations need to be further confirmed by a large, multicenter, randomized clinical trial., Clinical Trials Registration: NCT03620370., Classification of Evidence: This pilot study provides Class I evidence that NBO combined with standard EVT decreases infarction volume in patients with acute anterior circulation stroke., (© 2022 American Academy of Neurology.)

Neurogenesis plays an important role in the prognosis of stroke patients and is known to be promoted by the activation of the Notch1 signaling pathway. Studies on the airway epithelium have shown that miR-449b represses the Notch pathway. The study aimed to investigate whether limb remote ischemic conditioning (LRIC) was able to promote neurogenesis in cerebral ischemic mice, and to investigate the role of the miR-449b/Notch1 pathway in LRIC-induced neuroprotection. Male C57BL/6 mice (22-25 g) were subjected to transient middle cerebral artery occlusion (MCAO), and LRIC was performed in the bilateral lower limbs immediately after MCA occlusion. Immunofluorescence staining was performed to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 8% O 2 . After LRIC treatment on day 28, mice recovered neurological function. Neuronal precursor proliferation was enhanced in the SVZ, and neuronal precursor migration was enhanced in the basal ganglia on day 7. LRIC promoted the improvement of neurological function in mice on day 28, promoted neuronal precursor proliferation in the SVZ, and enhanced neuronal precursor migration in the basal ganglia on day 7. The neurological function score was negatively correlated with the number of BrdU-positive/DCX-positive cells in the SVZ and striatum. LRIC promoted activated Notch1 protein expression in the SVZ and substantially downregulated miR-449b levels in the SVZ and plasma. In vitro, miR-449b was found to target Notch1. Lentivirus-mediated miR-449b knockdown increased Notch1 levels in NE-4C cells and increased proliferation in the cells. The effects of miR-449b inhibition on neurogenesis were ablated by the application of Notch1 shRNA. Our study showed that LRIC promoted the proliferation and migration of neural stem cells after MCAO, and these effects were modulated by the miR-449b/Notch1 pathway.

Aims: Early neurological deterioration (END) is an important factor that affects prognosis in patients with acute ischemic stroke. We explored the relationship between serum occludin levels after successful reperfusion and END in patients treated with endovascular thrombectomy (EVT)., Methods: We prospectively enrolled 120 stroke patients who underwent EVT with successful reperfusion. Enzyme-linked immunosorbent assay was used to detect the serum occludin levels on admission and within 1 h after successful reperfusion. Receiver operating characteristic curves (ROC) and regression analysis were used to compare the relationship between serum occludin and END after thrombectomy., Results: Among the 120 patients, 36 (30%) experienced END. The END group had higher serum occludin levels than the non-END group after successful reperfusion [4.31 (3.71-5.38) vs 6.32 (5.88-6.99), p < 0.001]. The ROC curve showed that postoperative serum occludin levels had a significant prediction value for END (AUC: 0.86, p < 0.001). Regression analysis showed that serum occludin was an independent risk factor for END in EVT patients (adjusted odds ratio: 4.46, 95% confidence interval: 1.92-10.32; p < 0.001)., Conclusions: The higher serum occludin levels were strongly related to END after successful reperfusion. Serum occludin may be an independent risk factor for END in EVT patients., (© 2022 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Rationale: There are no randomized trials examining the best treatment for acute basilar artery occlusion in the 6-24-hour time window., Aims: To assess the safety and efficacy of thrombectomy for stroke due to basilar artery occlusion in patients randomized within 6-24 h from symptom onset or time last seen well., Sample Size: For an estimated difference of 20% in proportions of the primary outcome between the two groups, 318 patients will be included for 5% significance and 90% power with a planned interim analysis after two-thirds of the sample size (212 patients) have achieved the 90 days follow-up., Methods and Design: A prospective, multi-center, randomized, controlled, open-label and blinded-endpoint trial. The randomization employs a 1:1 ratio of mechanical thrombectomy with the detachable Solitaire thrombectomy device and best medical therapy (BMT) vs. BMT alone., Study Outcomes: The primary outcome will be the proportion of patients achieving modified Rankin Scale (mRS) 0-3 at 90 days. Key secondary outcomes are: dramatic early favorable response, dichotomized mRS score (0-2 vs. 3-6 and 0-4 vs. 5-6) at 90 days, ordinal (shift) mRS analysis at 90 days, infarct volume at 24 h, vessel recanalization at 24 h in both treatment arms, and successful recanalization in the thrombectomy arm according to the modified thrombolysis in cerebral infarction (mTICI) classification defined as mTICI 2 b or 3. Safety variables are mortality at 90 days, symptomatic intracranial hemorrhage rates at 24 h, and procedure-related complications., Discussion: Results from this trial will indicate whether mechanical thrombectomy is superior to medical management alone in achieving favorable outcomes in subjects with acute stroke caused by basilar artery occlusion presenting within 6-24 h from symptom onset. Trial registration: URL: http://www.clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT02737189.

Objective: Distant ischemic postconditioning (DIPC) has been confirmed to have a neuroprotective effect in animal models of ischemia. However, there are only a few studies on its efficacy and safety in clinical applications., Method: We divided 86 patients with acute non-cardiogenic mild to moderate cerebral infarction into DIPC and control groups., Result: After 7 days of using different pressure DIPC therapies, the National Institutes of Health Stroke Scale (NIHSS) scores on the eighth day significantly decreased, and modified Rankin scale significantly increased in the DIPC group, compared to that before treatment. On the eight day of admission, the decrease in the NIHSS scores significantly differed between the two groups. However, there was no change in the early neurological deterioration and platelet aggregation rates between the two groups on the eighth day., Conclusion: These results demonstrate that DIPC can safely and effectively improve neurological deficits in acute stages of mild to moderate cerebral infarction without affecting the efficacy of antiplatelet drugs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: To analyze the characteristics of acute ischemic stroke (AIS) resulting from moyamoya disease (MMD) and intracranial large artery atherosclerotic stenosis (LAS)., Method: This real-world case control study enrolled imaging-confirmed AIS patients owing to MMD or LAS hospitalized from January 2015 through September 2020 consecutively. The features of risk factors, peripheral blood, and imaging presentations were compared between the two cohorts., Results: A total of 191 eligible patients entered into final analysis, including 70 cases with MMD stroke and 121 with LAS stroke. LAS stroke vs. MMD stroke, the ratios of hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia were higher in the former (65.3 vs.12.9%, 65.3% vs. 4.3%, 39.7% vs. 2.9%, and 43.8% vs.12.9%; all p < 0.01) as well as baseline plasma arachidonic acid (AA) and adenosine diphosphate (ADP)-stimulated maximum platelet aggregation rates (75.3% vs. 60.8% and 73.1% vs.64.9%, respectively, all p < 0.01), which were positively correlated with triglycerides and cholesterol levels, blood glucose, age, and platelet counts (all p < 0.01). Classical watershed infarction (WSI) accounted for 87.14% in MMD stroke and 40.49% in LAS stroke, respectively (p < 0.01). Almost all of the patients with LAS showed plaques in arterial walls on CTA maps and non-homogeneous thickening with irregular luminal narrowing on HRMRI, while plaques were seldom found in MMD besides homogeneous thickening with regular luminal narrowing., Conclusions: Differing from LAS stroke, MMD stroke mainly presents with WSI and does not feature with platelet hyper-aggregation and fragmentation of ulcer plaque. Whereby, focusing on perfusion improvement rather than antiplatelets and statins may be the predominant step in MMD-stroke correction., (© 2021. Fondazione Società Italiana di Neurologia.)

Intra-arterial selective cooling infusion (IA-SCI) is a promising method for neuroprotection of patients with acute ischemic stroke. One shortcoming of IA-SCI is the elevated delivery temperature caused by the cold perfusate warming along the catheter pathway. Therefore, increasing the thermal resistance of the catheter is of significant importance. In this manuscript, an air-insulated catheter was designed and manufactured through extrusion molding technique. The computational fluid dynamics (CFD)-based thermo-/hemo-dynamics models were exploited to evaluate the thermal conductivity of the catheter. Compared with commercially available endovascular catheters, its thermal insulation property was analyzed through an in vitro experiment. The temperature of the 4°C perfusate (20 ml/min) increased to 14.2°C ± 0.2°C after being transferred to the distal tip of the air-insulated catheter, which was significantly lower than that (30°C) of commercially available alternatives. Moreover, the simulated blood (56% glycerin and 44% bi-distilled water, 37°C) in the middle cerebral artery of the artificial circulating system was cooled down to 29.7°C ± 0.1°C by this perfusate. The cooling process of the brain tissue was also estimated by a biological heat-transfer mathematical model, which showed a 2°C decrease within the initial 1 min infusion. This study demonstrated that the air-insulated catheter for IA-SCI was promising in vitro in terms of its high cooling efficiency and could be a competitive intervention catheter for therapeutic hypothermia., (Copyright © 2021. Published by Elsevier Ltd.)

Sleep disturbances are common in patients with stroke, and sleep quality has a critical role in the onset and outcome of stroke. Poor sleep exacerbates neurological injury, impedes nerve regeneration, and elicits serious complications. Thus, exploring a therapy suitable for patients with stroke and sleep disturbances is imperative. As a multi-targeted nonpharmacological intervention, remote ischemic conditioning can reduce the ischemic size of the brain, improve the functional outcome of stroke, and increase sleep duration. Preclinical/clinical evidence showed that this method can inhibit the inflammatory response, mediate the signal transductions of adenosine, activate the efferents of the vagal nerve, and reset the circadian clocks, all of which are involved in sleep regulation. In particular, cytokines tumor necrosis factor α (TNFα) and adenosine are sleep factors, and electrical vagal nerve stimulation can improve insomnia. On the basis of the common mechanisms of remote ischemic conditioning and sleep regulation, a causal relationship was proposed between remote ischemic conditioning and post-stroke sleep quality., (© 2021. Higher Education Press.)

Intravenous thrombolysis elevates the prognostic level of acute ischemic stroke (AIS) patients. Normobaric hyperoxia (NBO) delays the progression of the infarct core and promotes neurological recovery. However, it is uncertain whether NBO can further raise the prognostic level of AIS patients based on intravenous thrombolysis. To explore the efficacy and safety of NBO combined with intravenous thrombolysis on AIS patients. This observational study included anterior circulation stroke patients who received intravenous thrombolysis within 4.5 h after stroke onset. These patients were divided into two groups based on whether or not they received NBO therapy. The baseline data and the prognosis of the two groups were compared. The primary outcome was the proportion of functional independence (modified Rankin Scale 0-2) at 90 days post discharge. A total of 227 patients were included in this study. 125 patients received NBO therapy combined with intravenous thrombolysis, while 102 patients received intravenous thrombolysis only. Overall, the rate of recanalization was 83.3%. Consequently, 101 patients (80.8%) who received NBO combined with intravenous thrombolysis and 63 patients (61.8%) in the control group achieved functional independence (P = 0.002). Multivariable logistic regression analysis showed that NBO combined with intravenous thrombolysis over intravenous thrombolysis alone was associated with 90-day functional independence (OR: 2.318; 95% CI: 1.226-4.381; P = 0.01). This study verified the efficacy and safety of NBO combined with intravenous thrombolysis in AIS patients. Prospective study is needed to further substantiate these findings.

Background/aim: Stroke is among the most common causes of disability and death in highly developed countries and China. We sought to study the role of oleanolic acid in cerebral ischemia-reperfusion injury., Methods: Middle cerebral artery occlusion (MCAO) was performed to induce cerebral ischemia-reperfusion injury in mice. For the short-term effects of oleanolic acid (OA) against MCAO, mice administrated with OA (6 mg/kg /d) for 3 days before the injury were evaluated the infarct volume, neurological scores, blood brain barrier permeability and oxidative stress level, while for the long-term effects, MCAO mice were injected daily with OA for 6 weeks, followed by assessments of motor function, behavior and cerebral infarction area., Results: Pretreatment of oleanolic acid alleviated MCAO-induced ischemia-reperfusion injury as indicated by the significant decreases in cerebral infarction area and neurological symptom score at 24 h post injury, Evans blue leakage, expression of matrix metalloproteinase 9 (MMP9) and occludin, dihydroethidium fluorescence, and block malonaldehyde generation. In the long run, OA significantly reduced brain loss, enhanced the motor function, promoted the recovery of nerve function, and improved the learning and memory ability 9 weeks after the ischemia-reperfusion injury. OA also inhibited astrocytes proliferation and microglia activation, promoted the expression of synapse-related proteins, and increased the number of DCX+ cells in the hippocampus., Conclusions: OA exhibits both short-term and long-term protective effects against the cerebral ischemia-reperfusion injury in mice. The short-term protective mechanism is related to the anti-oxidation of blood-brain barrier, while the long-term protective effect lies in neuroglia modulation, promotion of synaptic connection and neuroregeneration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: Whether tirofiban is safe and effective in cardioembolic stroke patients treated with endovascular thrombectomy (EVT) remains unknown; this study evaluated the safety and efficacy of low-dose tirofiban in this patients population., Methods: This study was a prospective registry study. Patients with cardioembolic stroke undergoing EVT from January 2013 to December 2020 were treated with EVT alone or EVT plus low-dose tirofiban. The primary outcome was symptomatic intracerebral hemorrhage (sICH) prior to discharge. The secondary outcomes included reocclusion, in-hospital mortality, and 3-month functional outcomes., Results: Overall, 288 patients were recruited and 117 received low-dose tirofiban; 137 patients (47.6%) experienced ICH, 42 patients (14.6%) were sICH, and 23 patients (8%) were fatal ICH. Thirteen patients (11.1%) receiving tirofiban and 29 patients (17.0%) not receiving tirofiban experienced sICH (p = 0.167). Reocclusion occurred in nine patients (7.7%) receiving tirofiban and 15 patients (8.8%) not receiving tirofiban (p = 0.745). The rates of hernia (6.8% versus 20.5%) and decompressive craniectomy (2.6% versus 11.7%) were significantly lower in patients receiving tirofiban (p < 0.01). At 3-month follow-up, functional independence was achieved in 39 patients(33.3%) receiving tirofiban and 43 patients (25.1%) not receiving tirofiban (p = 0.131). Tirofiban was associated with lower odds of in-hospital mortality (3.4% versus 12.3%; adjusted odds ratio, 0.16; 95% confidence interval, 0.03-0.81; adjusted p = 0.027)., Conclusions: In patients with cardioembolic stroke undergoing EVT, tirofiban is not associated with higher sICH, it seems to lead to lower odds of in-hospital death. Further investigations are needed to confirm these results and to determine the optimal treatment protocols of tirofiban., (Copyright © 2021. Published by Elsevier B.V.)

Background: Animal and clinical studies have shown that remote ischemic conditioning (RIC) has protective effects for cerebral vascular diseases, with induced humoral factor changes in the peripheral blood. However, many findings are heterogeneous, perhaps due to differences in the RIC intervention schemes, enrolled populations, and sample times. This study aimed to examine the RIC-induced changes in the plasma proteome using rhesus monkey models of strokes., Methods: Two adult rhesus monkeys with autologous blood clot-induced middle cerebral artery (MCA) occlusion underwent RIC interventions twice a week for five consecutive weeks. Each RIC treatment included five cycles of five minutes of ischemia alternating with five minutes of reperfusion of the forearm. The blood samples were taken from the median cubital vein of the monkeys at baseline and immediately after each week's RIC stimulus. The plasma samples were isolated for a proteomic analysis using mass spectrometry (MS)., Results: Several proteins related to lipid metabolism (Apolipoprotein A-II and Apolipoprotein C-II), coagulation (Fibrinogen alpha chain and serpin), immunoinflammatory responses (complement C3 and C1), and endovascular hemostasis (basement membrane-specific heparan sulfate proteoglycan) were significantly modulated after the RIC intervention. Many of these induced changes, such as in the lipid metabolism regulation and anticoagulation responses, starting as early as two weeks following the RIC intervention. The complementary activation and protection of the endovascular cells occurred more than three weeks postintervention., Conclusions: Multiple protective effects were induced by RIC and involved lipid metabolism regulation (anti-atherogenesis), anticoagulation (antithrombosis), complement activation, and endovascular homeostasis (anti-inflammation). In conclusion, this study indicates that RIC results in significant modulations of the plasma proteome. It also provides ideas for future research and screening targets.

In order to rescue neuronal function, neuroprotection should be required not only for the neuron soma but also the dendrites. Here, we propose the hypothesis that ephrin-B2-EphB2 signaling may be involved in dendritic degeneration after ischemic injury. A mouse model of focal cerebral ischemia with middle cerebral artery occlusion (MCAO) method was used for EphB2 signaling test in vivo. Primary cortical neuron culture and oxygen-glucose deprivation were used to assess EphB2 signaling in vitro. siRNA and soluble ephrin-B2 ectodomain were used to block ephrin-B2-Ephb2 signaling. In the mouse model of focal cerebral ischemia and in neurons subjected to oxygen-glucose deprivation, clustering of ephrin-B2 with its receptor EphB2 was detected. Phosphorylation of EphB2 suggested activation of this signaling pathway. RNA silencing of EphB2 prevented neuronal death and preserved dendritic length. To assess therapeutic potential, we compared the soluble EphB2 ectodomain with the NMDA antagonist MK801 in neurons after oxygen-glucose deprivation. Both agents equally reduced lactate dehydrogenase release as a general marker of neurotoxicity. However, only soluble EphB2 ectodomain protected the dendrites. These findings provide a proof of concept that ephrin-B2-EphB2 signaling may represent a novel therapeutic target to protect both the neuron soma as well as dendrites against ischemic injury.

There remain debates on neuroprotection and rehabilitation techniques for acute ischemic stroke patients. Therapeutic physical exercise following stroke has shown promise but is challenging to apply clinically. Ischemic conditioning, which has several clinical advantages, is a potential neuroprotective method for stroke rehabilitation that is less understood. In the present study, the rehabilitative properties and mechanisms of physical exercise and remote ischemic postconditioning (RIPostC) after stroke were compared and determined. A total of 248 adult male Sprague-Dawley rats were divided into five groups: (1) sham, (2) stroke, (3) stroke with intense treadmill exercise, (4) stroke with mild treadmill exercise, and (5) stroke with RIPostC. Focal ischemia was evaluated by infarct volume and neurological deficit. Long-term functional outcomes were represented through neurobehavioral function tests: adhesive removal, beam balance, forelimb placing, grid walk, rota-rod, and Morris water maze. To further understand the mechanisms underlying neurorehabilitation and verify the presence thereof, we measured mRNA and protein levels of neuroplasticity factors, synaptic proteins, angiogenesis factors, and regulation molecules, including HIF-1α, BDNF, TrkB, and CREB. The key role of HIF-1α was elucidated by using the inhibitor, YC-1. Both exercise intensities and RIPostC significantly decreased infarct volumes and neurological deficits and outperformed the stroke group in the neurobehavioral function tests. All treatment groups showed significant increases in mRNA and protein expression levels of the target molecules for neurogenesis, synaptogenesis, and angiogenesis, with intermittent further increases in the RIPostC group. HIF-1α inhibition nullified most beneficial effects and indicative molecule expressions, including HIF-1α, BDNF, TrkB, and CREB, in both procedures. RIPostC is equally, or superiorly, effective in inducing neuroprotection and rehabilitation compared to exercise in ischemic rats. HIF-1α likely plays an important role in the efficacy of neuroplasticity conditioning, possibly through HIF-1α/BDNF/TrkB/CREB regulation.

Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly increased in cortical neurons after stroke. We synthesized a small peptide, Trans-trans-activating (Tat)-cold-inducible RNA binding protein (Tat-CIRP), which perturbed the function of MD2 and strongly protected neurons against excitotoxic injury in vitro. In addition, systemic administration of Tat-CIRP or genetic deletion of MD2 induced robust neuroprotection against ischemic and hemorrhagic stroke in mice. Tat-CIRP reduced the brain infarct volume and preserved neurological function in rhesus monkeys 30 days after ischemic stroke. Tat-CIRP efficiently crossed the blood-brain barrier and showed a wide therapeutic index for stroke because no toxicity was detected when high doses were administered to the mice. Furthermore, we demonstrated that MD2 elicited neuronal apoptosis and necroptosis via a TLR4-independent, Sam68-related cascade. In summary, Tat-CIRP provides robust neuroprotection against stroke in rodents and gyrencephalic nonhuman primates. Further efforts should be made to translate these findings to treat both ischemic and hemorrhagic stroke in patients., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Oxygen supply for ischemic brain tissue during stroke is critical to neuroprotection. Remote ischemic conditioning (RIC) treatment is effective for stroke. However, it is not known whether RIC can improve brain tissue oxygen supply. In current study, we employed a mouse model of stroke created by middle cerebral artery occlusion (MCAO) to investigate the effect of RIC on oxygen supply to the ischemic brain tissue using a hypoxyprobe system. Erythrocyte oxygen-carrying capacity and tissue oxygen exchange were assessed by measuring oxygenated hemoglobin and oxygen dissociation curve. We found that RIC significantly mitigated hypoxic signals and decreased neural cell death, thereby preserving neurological functions. The tissue oxygen exchange was markedly enhanced, along with the elevated hemoglobin P50 and right-shifted oxygen dissociation curve. Intriguingly, RIC markedly elevated 2,3-biphosphoglycerate (2,3-BPG) levels in erythrocyte, and the erythrocyte 2,3-BPG levels were highly negatively correlated with the hypoxia in the ischemic brain tissue. Further, adoptive transfusion of 2,3-BPG-rich erythrocytes prepared from RIC-treated mice significantly enhanced the oxygen supply to the ischemic tissue in MCAO mouse model. Collectively, RIC protects against ischemic stroke through improving oxygen supply to the ischemic brain tissue where the enhanced tissue oxygen delivery and exchange by RIC-induced 2,3-BPG-rich erythrocytes may play a role.

The aim of this study was to identify the ultrasound-based carotid plaque characteristics associated with new cerebral ischemic lesions after carotid endarterectomy (CEA). Between January 2013 and December 2018, carotid duplex ultrasound was performed in 1061 patients who underwent CEA. Brain magnetic resonance diffusion-weighted imaging (DWI) was performed pre-operatively and within 30 d after CEA. New cerebral ischemic lesions on DWI were observed in 169 patients. The cutoff value gray-scale median (GSM) used to distinguish DWI-positive from DWI-negative patients was 30.5, with an area under the receiver operating characteristic curve of 0.837. A larger proportion of multiple DWI lesions were observed in the GSM ≤30.5 group (59.5% vs. 41.5%, p = 0.030). Univariate and multivariate analyses identified GSM ≤30.5, ulcerated carotid plaques and pre-operative ischemic symptoms as predictors of post-operative cerebral DWI lesions. Our results indicate that ultrasound-based carotid plaque characteristics help predict new cerebral ischemic lesions after CEA., Competing Interests: Conflict of interest disclosure The authors declare that they have no conflicts of interest., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Ischemic stroke initiated by transient or permanent cerebral blood flow decline remains the leading cause of permanent disability in industrialized nations. Therapeutic strategies to improve patient recovery are remain limited. Hypoxia post-conditioning (HPostC) has been known to be neuroprotective against ischemic injuries in vivo and in vitro. Understanding its mechanism of action may promote its clinical translation. In this study, we devised a method of HPostC treatment to provide protection from a focal cerebral ischemic induced injury and to explore the underling mechanism. We found that our HPostC method improved energy supply by elevating the level of glucose, pyruvate and ATP/ADP ratio within the cerebral hemisphere in mice. In the distal middle cerebral artery occlusion (dMCAO) mice, this HPostC treatment reduced infarct size, and was associated with increased levels of pyruvate, pyruvate/lactate ratio and ATP/ADP ratio. Western blot analysis indicated that the HPostC treatment up-regulated AMPK signaling activities in the cerebral hemisphere. Our results suggest that this HPostC treatment exerts its neuroprotective effect by promoting glycolysis to elevate the ATP/ADP level, and the AMPK/PFKFB3 signaling pathway. These findings may provide biomarkers for clinical use of HPostC methods., (Copyright © 2020. Published by Elsevier B.V.)

Objective: The optimal anesthetic approach during endovascular therapy (EVT) in acute stroke patients remains an area of uncertainty. We investigated the impact of different anesthetic approaches on the outcome of posterior circulation stroke (PCS) patients undergoing EVT., Methods: For this observational study, we enrolled consecutive PCS patients who underwent EVT from December 2012 to December 2018, and compared functional outcomes at 90 days as well as long-term follow-up in patients treated under local anesthesia (LA) versus general anesthesia (GA). Multivariable logistic regression and propensity score matched analyses were conducted., Results: Among the 183 patients included in this study, 71 patients (38.8%) received LA and 112 patients (61.2%) received GA. Median modified Rankin Scale score at 90 days was 4 (IQR, 2-6) in both groups (P = .956). No significant differences in the rates of functional independence and mortality at 90 days as well as long-term follow-up post intervention were observed between the two groups, and Kaplan-Meier survival analysis showed comparable long-term survival probabilities. Safety outcomes (including procedure-related complications and serious adverse events) did not differ between these patients. The anesthetic approach was neither associated with functional independence nor associated with mortality. Propensity score matched analysis indicated similar results., Conclusions: For PCS patients undergoing EVT, LA compared with GA does not seem to result in different functional outcomes and complications rates., (Copyright © 2020 Elsevier B.V. All rights reserved.)