Improvement In Neurological Outcome Research Articles

Improvement in neurological outcome and brain hemodynamics after late cranioplasty.

Early cranioplasty has been encouraged after decompressive craniectomy (DC), aiming to reduce consequences of atmospheric pressure over the opened skull. However, this practice may not be often available in low-middle-income countries (LMICs). We evaluated clinical improvement, hemodynamic changes in each hemisphere, and the hemodynamic balance between hemispheres after late cranioplasty in a LMIC, as the institution's routine resources allowed. Prospective cohort study included patients with bone defects after DC evaluated with perfusion tomography (PCT) and transcranial Doppler (TCD) and performed neurological examinations with prognostic scales (mRS, MMSE, and Barthel Index) before and 6months after surgery. A final sample of 26 patients was analyzed. Satisfactory improvement of neurological outcome was observed, as well as significant improvement in the mRS (p = 0.005), MMSE (p < 0.001), and Barthel Index (p = 0.002). Outpatient waiting time for cranioplasty was 15.23 (SD 17.66) months. PCT showed a significant decrease in the mean transit time (MTT) and cerebral blood volume (CBV) only on the operated side. Although most previous studies have shown an increase in cerebral blood flow (CBF), we noticed a slight and nonsignificant decrease, despite a significant increase in the middle cerebral artery flow velocity in both hemispheres on TCD. There was a moderate correlation between the MTT and contralateral muscle strength (r = - 0.4; p = 0.034), as well as between TCD and neurological outcomes ipsilateral (MMSE; r = 0.54, p = 0.03) and contralateral (MRS; p = 0.031, r = - 0.48) to the operated side. Even 1year after DC, cranioplasty may improve cerebral perfusion and neurological outcomes and should be encouraged.

Depression of Pyroptosis by Inhibiting Caspase-1 Activation Improves Neurological Outcomes of Kernicterus Model Rats.

Kernicterus is a severe complication of extreme neonatal hyperbilirubinemia. Prolonged exposure to high-level unconjugated bilirubin (UCB) directly damages brain tissue. Neuroinflammation is believed to contribute to UCB-induced neurotoxicity. Pyroptosis has been as a highly inflammatory form of programmed cell death. Therefore, this study aimed to explore whether pyroptosis was involved in the pathogenesis of UCB neurotoxicity in kernicterus model rats. VX-765, a specific inhibitor of caspase-1, was intraperitoneally administered to the model rats to observe its effects on the short-term and long-term outcomes of the model animals at the molecular, cellular, morphological, and behavioral levels. The results indicated that UCB significantly induced the activation of caspase-1 and gasdermin D(GSDMD), and VX-765 inhibited caspase-1-GSDMD pathway. Compared with those of the UCB group and the vehicle+UCB group, VX-765-treated rats released lower levels of IL-1β and IL-18. Furthermore, H&E and TUNEL staining showed that nerve cells in the VX-765-treated group were better preserved and had less DNA fragmentation. Most importantly, VX-765 improved both the short-term and long-term neurological functions of kernicterus model rats. This study demonstrated that pyroptosis was involved in the pathogenesis of kernicterus through caspase-1 activation, which could be inhibited by VX-765, exerting a neuroprotective effect in kernicterus model rats.

Aqueous extract of Terminalia arjuna bark attenuates blood brain barrier disruption in rat model of transient focal cerebral ischemia

BackgroundTerminalia arjuna (TA) is a widely used medicinal plant in Indian traditional medicinal system. In the Ayurvedic system of medicine it is used as a cardiotonic and also well documented in experimental studies for its efficacy in various cardiac ailments. Few recent studies have reported its neuroprotective effects in rat model of cerebral ischemia. However, the effect of TA on cerebral ischemia induced Blood brain barrier (BBB) damage is still unclear. PurposeThe present study is aimed to evaluate the ameliorative effect of aqueous extract of Terminalia arjuna (aeTA) against transient focal cerebral ischemia induced BBB damage. Study designAdult male Sprague-dawley rats (270–300g) were randomly divided into three groups: Sham, Lesion (Middle cerebral artery occlusion for 2 hours) and aeTA pre-treatment at a dose of 500 mg /kg body weight/day orally for 15 days prior to MCAo. Materials and MethodsAfter 24 h of ischemic-reperfusion injury, the rats were assessed for behavioral deficits by Modified neurological severity scoring (mNSS), infarct measurement by Triphenyl tetrazolium chloride (TTC) staining, BBB integrity by Evans blue (EB) staining, protein and mRNA expressions of TJ proteins (Claudin5 & Occludin), MMPs (MMP2 & MMP9) and TIMPs (TIMP1 & TIMP2) through western blot analysis and real time PCR. ResultsThe pre-treatment with aeTA for 15 days exhibited significant improvement in neurological outcome and reduced infarct volume compared with the MCAo rats. The aeTA treatment also reduced the BBB damage which was confirmed through decreased EB extravasations, significant reduction in protein levels of MMPs (MMP2 &MMP9) and maintaining the protein levels of tight junction proteins. We also found that aeTA treatment downregulated the mRNA levels of MMPs and upregulated mRNA expression levels of TIMPs and tight junction proteins (Claudin5 & Occludin). ConclusionThese results demonstrate the neuroprotective property of aeTA treatment by reducing the MMPs mediated BBB damage after focal cerebral ischemia.

Lactulose Improves Neurological Outcomes by Repressing Harmful Bacteria and Regulating Inflammatory Reactions in Mice After Stroke.

Background and ObjectiveGut microbiota dysbiosis following stroke affects the recovery of neurological function. Administration of prebiotics to counteract post-stroke dysbiosis may be a potential therapeutic strategy to improve neurological function. We aim to observe the effect of lactulose on neurological function outcomes, gut microbiota composition, and plasma metabolites in mice after stroke.MethodsMale C57BL/6 mice (20–25 g) were randomly divided into three groups: healthy control, photothrombotic stroke + triple-distilled water, and photothrombotic stroke + lactulose. After 14 consecutive days of lactulose administration, feces, plasma, and organs were collected. 16S rDNA sequencing, plasma untargeted metabolomics, qPCR, flow cytometry and Elisa were performed.ResultsLactulose supplementation significantly improved the functional outcome of stroke, downregulated inflammatory reaction, and increased anti-inflammatory factors in both the brain and gut. In addition, lactulose supplementation repaired intestinal barrier injury, improved gut microbiota dysbiosis, and partially amended metabolic disorder after stroke.ConclusionLactulose promotes functional outcomes after stroke in mice, which may be attributable to repressing harmful bacteria, and metabolic disorder, repairing gut barrier disruption, and reducing inflammatory reactions after stroke.

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice.

Microvascular failure is one of the key pathogenic factors in the dynamic pathological evolution after traumatic brain injury (TBI). Our laboratory and others previously reported that Annexin A2 functions in blood-brain barrier (BBB) development and cerebral angiogenesis, and recombinant human Annexin A2 (rA2) protected against hypoxia plus IL-1β-induced cerebral trans-endothelial permeability in vitro, and cerebral angiogenesis impairment of AXNA2 knock-out mice in vivo. We thereby hypothesized that ANXA2 might be a cerebrovascular therapy candidate that targets early BBB integrity disruption, and subacute/delayed cerebrovascular remodeling after TBI, ultimately improve neurological outcomes. In a controlled cortex impact (CCI) mice model, we found rA2 treatment (1 mg/kg) significantly reduced early BBB disruption at 24 h after TBI; and rA2 daily treatment for 7 days augmented TBI-induced mRNA levels of pro-angiogenic and endothelial-derived trophic factors in cerebral microvessels. In cultured human brain microvascular endothelial cells (HBMEC), through MAPKs array, we identified that rA2 significantly activated Akt, ERK, and CREB, and the activated CREB might be responsible for the rA2-induced VEGF and BDNF expression. Moreover, rA2 administration significantly increased cerebral angiogenesis examined at 14 days and vessel density at 28 days after TBI in mice. Consistently, our results validated that rA2 significantly induced angiogenesis in vitro, evidenced by tube formation and scratched migration assays in HBMEC. Lastly, we demonstrated that rA2 improved long-term sensorimotor and cognitive function, and reduced brain tissue loss at 28 days after TBI. Our findings suggest that rA2 might be a novel vascular targeting approach for treating TBI.

Does Targeted Temperature Management Improve Neurological Outcome in Extracorporeal Cardiopulmonary Resuscitation (ECPR)?

Targeted temperature management (TTM) is a standard of care in patients after cardiac arrest for neuroprotection. Currently, the effectiveness and efficacy of TTM after extracorporeal cardiopulmonary resuscitation (ECPR) is unknown. We aimed to compare neurological and survival outcomes between TTM vs non-TTM in patients undergoing ECPR for refractory cardiac arrest. We searched PubMed and 5 other databases for randomized controlled trials and observational studies reporting neurological outcomes or survival in adult patients undergoing ECPR with or without TTM. Good neurological outcome was defined as cerebral performance category <3. Two independent reviewers extracted the data. Random-effects meta-analyses were used to pool data. We included 35 studies (n = 2,643) with the median age of 56 years (interquartile range [IQR]: 52-59). The median time from collapse to ECMO cannulation was 58 minutes (IQR: 49-82) and the median ECMO duration was 3 days (IQR: 2.0-4.1). Of 2,643, 1,329 (50.3%) patients received TTM and 1,314 (49.7%) did not. There was no difference in the frequency of good neurological outcome at any time between TTM (29%, 95% confidence interval [CI]: 23%-36%) vs. without TTM (19%, 95% CI: 9%-31%) in patients with ECPR (P = 0.09). Similarly, there was no difference in overall survival between patients with TTM (30%, 95% CI: 22%-39%) vs. without TTM (24%, 95% CI: 14%-34%) (P = 0.31). A cumulative meta-analysis by publication year showed improved neurological and survival outcomes over time. Among ECPR patients, survival and neurological outcome were not different between those with TTM vs. without TTM. Our study suggests that neurological and survival outcome are improving over time as ECPR therapy is more widely used. Our results were limited by the heterogeneity of included studies and further research with granular temperature data is necessary to assess the benefit and risk of TTM in ECPR population.

NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury

Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.

Comparison of Minimally Invasive Total versus Subtotal Resection of Spinal Tumors: A Systematic Review and Meta-Analysis

With the advent of minimally invasive techniques, minimally invasive spine surgery (MISS) has become a realistic option for many spine cases. This study aims to evaluate the operative and clinical outcomes of MISS for total versus subtotal tumor resection from current evidence. A literature search was performed using the search term (Minimally invasive surgery OR MIS) AND (spine tumor OR spinal tumor). Studies including both minimally invasive total and subtotal resection cases with operative or clinical data were included. Seven studies describing 159 spinal tumor cases were included. Compared with total resection, subtotal resection showed no significant differences in surgical time (mean difference (MD), 9.44 minutes; 95% confidence interval [CI], -47.66 to 66.55 minutes; P= 0.37), surgical blood loss (MD, -84.72 mL; 95% CI, -342.82 to 173.39 mL; P= 0.34), length of stay (MD, 1.38 days; 95% CI, -0.95 to 3.71 days; P= 0.17), and complication rate (odds ratio, 9.47; 95% CI, 0.34-263.56; P= 0.12). Pooled analyses with the random-effects model showed that neurologic function improved in 89% of patients undergoing total resection, whereas neurologic function improved in 61% of patients undergoing subtotal resection. Our analyses show that there is no significant difference in operative outcomes between total and subtotal resection. Patients undergoing total resection showed slightly better improvement in neurologic outcomes compared with patients undergoing subtotal resection. Overall, this study suggests that both total and subtotal resection may result in comparable outcomes for patients with spinal tumors. However, maximal safe resection remains the ideal treatment because it provides the greatest chance of long-term benefit.

Adrenaline to improve survival in out-of-hospital cardiac arrest: the PARAMEDIC2 RCT.

Adrenaline has been used as a treatment for cardiac arrest for many years, despite uncertainty about its effects on long-term outcomes and concerns that it may cause worse neurological outcomes. The objectives were to evaluate the effects of adrenaline on survival and neurological outcomes, and to assess the cost-effectiveness of adrenaline use. This was a pragmatic, randomised, allocation-concealed, placebo-controlled, parallel-group superiority trial and economic evaluation. Costs are expressed in Great British pounds and reported in 2016/17 prices. This trial was set in five NHS ambulance services in England and Wales. Adults treated for an out-of-hospital cardiac arrest were included. Patients were ineligible if they were pregnant, if they were aged < 16 years, if the cardiac arrest had been caused by anaphylaxis or life-threatening asthma, or if adrenaline had already been given. Participants were randomised to either adrenaline (1 mg) or placebo in a 1 : 1 allocation ratio by the opening of allocation-concealed treatment packs. The primary outcome was survival to 30 days. The secondary outcomes were survival to hospital admission, survival to hospital discharge, survival at 3, 6 and 12 months, neurological outcomes and health-related quality of life through to 6 months. The economic evaluation assessed the incremental cost per quality-adjusted life-year gained from the perspective of the NHS and Personal Social Services. Participants, clinical teams and those assessing patient outcomes were masked to the treatment allocation. From December 2014 to October 2017, 8014 participants were assigned to the adrenaline (n = 4015) or to the placebo (n = 3999) arm. At 30 days, 130 out of 4012 participants (3.2%) in the adrenaline arm and 94 out of 3995 (2.4%) in the placebo arm were alive (adjusted odds ratio for survival 1.47, 95% confidence interval 1.09 to 1.97). For secondary outcomes, survival to hospital admission was higher for those receiving adrenaline than for those receiving placebo (23.6% vs. 8.0%; adjusted odds ratio 3.83, 95% confidence interval 3.30 to 4.43). The rate of favourable neurological outcome at hospital discharge was not significantly different between the arms (2.2% vs. 1.9%; adjusted odds ratio 1.19, 95% confidence interval 0.85 to 1.68). The pattern of improved survival but no significant improvement in neurological outcomes continued through to 6 months. By 12 months, survival in the adrenaline arm was 2.7%, compared with 2.0% in the placebo arm (adjusted odds ratio 1.38, 95% confidence interval 1.00 to 1.92). An adjusted subgroup analysis did not identify significant interactions. The incremental cost-effectiveness ratio for adrenaline was estimated at £1,693,003 per quality-adjusted life-year gained over the first 6 months after the cardiac arrest event and £81,070 per quality-adjusted life-year gained over the lifetime of survivors. Additional economic analyses estimated incremental cost-effectiveness ratios for adrenaline at £982,880 per percentage point increase in overall survival and £377,232 per percentage point increase in neurological outcomes over the first 6 months after the cardiac arrest. The estimate for survival with a favourable neurological outcome is imprecise because of the small numbers of patients surviving with a good outcome. Adrenaline improved long-term survival, but there was no evidence that it significantly improved neurological outcomes. The incremental cost-effectiveness ratio per quality-adjusted life-year exceeds the threshold of £20,000-30,000 per quality-adjusted life-year usually supported by the NHS. Further research is required to better understand patients' preferences in relation to survival and neurological outcomes after out-of-hospital cardiac arrest and to aid interpretation of the trial findings from a patient and public perspective. Current Controlled Trials ISRCTN73485024 and EudraCT 2014-000792-11. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 25. See the NIHR Journals Library website for further project information.

Androgen is responsible for enhanced susceptibility of melatonin against traumatic brain injury in females

BackgroundNumerous publications have demonstrated that melatonin administration is associated with mortality reduction and improvement in neurological outcomes after traumatic brain injury (TBI). However, there are significant sex differences in several diseases associated with melatonin. We aimed to determine whether androgen was responsible for enhanced susceptibility of melatonin against TBI in females, as well as potential molecular mechanisms. MethodsWeight-drop was used to establish a rodent model of TBI. Melatonin (10 mg/kg) and testosterone (1 mg/kg) were administered three times every day for three days after TBI using subcutaneous injection, respectively. Seven days after TBI, an open field assay was used to evaluate locomotor and exploratory activities. Neuronal amount, neuronal apoptosis, and expression of phosphorylated extracellularly regulated protein kinases 1/2 (ERK1/2), c-jun N-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (p38MAPK) in neurons were assessed using immunofluorescence assay seven days after TBI. The expression of caspase-3, Bax, and Bcl-2 in the frontal cortex was detected using western blot. ResultsCompared with female rats, melatonin administration exhibited more neuroprotective effects (including improved locomotor and exploratory activities, elevated neuronal amount, and reduced neuronal apoptosis) in male rats exposed to TBI. Moreover, testosterone significantly improved locomotor and exploratory activities, elevated neuronal amount, decreased neuronal apoptosis, downregulated phosphorylation of JNK1/2- and p38MAPK-positive neurons, but upregulated phosphorylation of ERK1/2-positive neurons in the frontal cortex, and reduced the expressions of cleaved caspase-3, Bax, but increased Bcl-2 expressions in female rats exposed to TBI. ConclusionsAndrogen was responsible for the enhanced susceptibility to TBI under melatonin supplementation in females through a mechanism that may be associated with MAPK pathway regulation.

Antiplatelet Therapy in the Secondary Prevention of Non-cardioembolic Ischemic Stroke and Transient Ischemic Attack: A Mini-Review.

The aim of this mini-review is to discuss the main antiplatelet agents that have been successfully used in the secondary prevention of non-cardioembolic ischemic stroke and transient ischemic attacks (TIA). The methodology is based on a literature review of available peer-reviewed English studies listed in PubMed. The findings reveal that aspirin remains a reliable antiplatelet agent in the secondary prevention of acute non-cardioembolic ischemic stroke and TIA. Nevertheless, currently, there are also other agents, i.e., ticagrelor, clopidogrel, and cilostazol, that can be applied. In addition, the results indicate that time is significant not only in severe stroke but also in non-severe stroke and TIA, which suggests that antiplatelet therapy should be applied within 24 h after the first symptoms because early treatment can lead to an improvement in neurological outcomes and reduce the chance of an early subsequent stroke.

Shorter Interval from Witnessed Out-Of-Hospital Cardiac Arrest to Reaching the Target Temperature Could Improve Neurological Outcomes After Extracorporeal Cardiopulmonary Resuscitation with Target Temperature Management: A Retrospective Analysis of a Japanese Nationwide Multicenter Observational Registry.

Extracorporeal cardiopulmonary resuscitation (ECPR) with extracorporeal membrane oxygenation is a more promising treatment for out-of-hospital cardiac arrest (OHCA) than conventional cardiopulmonary resuscitation (CCPR). However, previous studies that compared ECPR and CCPR included mixed groups of patients with or without target temperature management (TTM). In this study, we compared the neurological outcomes of OHCA between ECPR and CCPR with TTM in all patients. We performed retrospective subanalyses of the Japanese Association for Acute Medicine OHCA registry. Witnessed adult cases of cardiogenic OHCA treated with TTM were eligible for this study. We used univariate and multivariable analyses in all eligible patients to compare the neurological outcomes after ECPR or CCPR. We also conducted propensity score analyses of all patients and according to the interval from witnessed OHCA to reaching the target temperature (IWT) of ≤600, ≤480, ≤360, ≤240, and ≤120 minutes. We analyzed 1146 cases. The propensity score analysis did not show a significant difference in favorable neurological outcomes (defined as a Glasgow-Pittsburgh Cerebral Performance Category of 1-2 at 1 month after collapse) between EPCR and CCPR (odds ratio: OR 4.683 [95% confidence interval: CI 0.859-25.535], p = 0.747). However, ECPR was associated with more favorable neurological outcomes in patients with IWT of ≤600 minutes (OR 7.089 [95% CI 1.091-46.061], p = 0.406), ≤480 minutes (OR 10.492 [95% CI 1.534-71.773], p = 0.0168), ≤360 minutes (OR 17.573 [95% CI 2.486-124.233], p = 0.0042), ≤240 minutes (OR 38.908 [95% CI 5.045-300.089], p = 0.0005), and ≤120 minutes (OR 200.390 [95% CI 23.730-1692.211], p < 0.001). This study revealed significant differences in the neurological outcomes between ECPR and CCPR in patients with TTM whose IWT was ≤600 minutes.

Abstract 346: Targeted Temperature Management is Associated with Improved Neurological Outcomes in Witnessed Out-of-hospital Cardiac Arrest Patients Who Achieve Early Return of Spontaneous Circulation

Background: Previous randomized controlled trials demonstrated the efficacy of targeted temperature management (TTM) in out-of-hospital cardiac arrest (OHCA) patients with both shockable and non-shockable rhythm. Real-world evidence for TTM using large OHCA database are scarce, and no study has investigated the relationship between TTM and time-to-return of spontaneous circulation (ROSC). Methods: The Japanese Association for Acute Medicine - out-of-hospital cardiac arrest (JAAM-OHCA) Registry is a multicenter, prospective, observational registry including 34,754 OHCA patients between 2014 and 2017. Patients with witnessed non-traumatic OHCA who had been resuscitated and were in a coma were included. Eligible patients were divided into two groups according to the use of TTM. The primary outcome was defined as a Cerebral Performance Categories (CPC) Scale 1-2 at 30 days after OHCA. The propensity score matching analysis was used. The cubic spline analysis of the odds ratio of CPC 1-2 for TTM use by time-to-ROSC was performed. Results: Out of 34,754 patients with OHCA, 5,261 patients were included. The mean age was 70.3 years, and 3,417 (65.0%) were male. CPC 1-2 was more frequently observed in the TTM group in propensity score matching analysis (15.1% vs. 8.5%; odds ratio 1.92; 95% confidence interval 1.04-3.53; P=0.037). The cubic spline analysis showed that TTM was associated with CPC 1-2 in witnessed OHCA patients, which did not reach statistical significance in patients with time-to-ROSC longer than 50 min. Conclusions: TTM was associated with better neurological outcomes in witnessed OHCA patients, especially when patients were resuscitated within 50 min after collapse.

Metabolic Epilepsy.

Inborn errors of metabolism have been considered as an infrequent cause of epilepsy. Improvement in diagnostics has improved the detection of a metabolic basis of recurrent seizures in neonates and children. The term 'metabolic epilepsy' is used to suggest inherited metabolic disorders with predominant epileptic manifestations as well as those where epilepsy is part of the overall neurological phenotype. Several of these disorders are treatable, and the physician should bear in mind the classical ages of presentation. As there are no specific clinical or electrographic features suggestive of metabolic epilepsies, an early suspicion is based on clinical and laboratory clues. Fortunately, with the advancement of gene sequencing technology, a diagnosis of these rare conditions is more straightforward and may not require invasive procedures such as biopsies, multiple metabolic stress-induced testing for abnormalities, and cerebrospinal fluid analysis. A gene panel may suffice in most cases and can be done from a blood sample. In many countries, many treatable metabolic disorders are now part of the neonatal screen. Early diagnosis and treatment of these disorders can result in the prevention of a full-scale metabolic crisis and improvement of neurological outcomes. Long-term neurological outcomes are variable and additional therapies may be required.

Determining Optimal Mean Arterial Pressure After Cardiac Arrest: A Systematic Review.

The use of cerebral autoregulation monitoring to identify patient-specific optimal mean arterial pressure (MAPOPT) has emerged as a technique to augment cerebral oxygen delivery in post-cardiac arrest patients. Our systematic review aims to determine (a) the average MAPOPT in these patients, (b) the feasibility of identifying MAPOPT, (c) the brain tissue oxygenation levels when MAP iswithin proximity to the MAPOPT and (d) the relationship between neurological outcome and MAPOPT-targeted resuscitation strategies. We carried out this review in accordance with the PRISMA guidelines. We included all studies that used cerebral autoregulation to determine MAPOPT in adult patients (> 16years old) who achieved return of spontaneous circulation (ROSC) following cardiac arrest. All studies had to include our primary outcome of MAPOPT. We excluded studies where the patients had any history of traumatic brain injury, ischemic stroke or intracranial hemorrhage. We identified six studies with 181 patients. There was wide variability in cerebral autoregulation monitoring methods, length of monitoring, calculation and reporting of MAPOPT. Amongst all studies, the median or mean MAPOPT was consistently above 65mmHg (range 70-114mmHg). Definitions of feasibility varied among studies and were difficult to summarize. Only one study noted that brain tissue oxygenation increased as patients' MAP approached MAPOPT. There was no consistent association between targeting MAPOPT and improvedneurological outcome. There is considerable heterogeneity in MAPOPT due to differences in monitoring methods of autoregulation. Further research is needed to assess the clinical utility of MAPOPT-guided strategies on decreasing secondary injury and improving neurological outcomes after ROSC.

Mechanical Thrombectomy for Acute Ischemic Stroke in the Cardiac Catheterization Laboratory

ObjectivesThe aim of this study was to determine the feasibility of establishing a mechanical thrombectomy (MT) program for acute ischemic stroke in a community hospital using interventional cardiologists working closely with neurologists. BackgroundAmerican Heart Association/American Stroke Association 2018 guidelines give a Class I (Level of Evidence: A) recommendation for MT in eligible patients with large vessel occlusion stroke. Improvement in neurological outcomes with MT is highly time sensitive. Most hospitals do not have trained neurointerventionalists to perform MT, leading to treatment delays that reduce the benefit of reperfusion therapy. MethodsAn MT program based in the cardiac catheterization laboratory was developed using interventional cardiologists with ST-segment elevation myocardial infarction teams. ResultsForty patients underwent attempted MT for acute ischemic stroke. An additional 5 patients who underwent angiography did not undergo attempted thrombectomy, because of absence of target thrombus (n = 4) or unsuitable anatomy (n = 1). Median National Institutes of Health Stroke Scale score prior to MT was 19 and at discharge was 7. TICI (Thrombolysis In Cerebral Infarction) grade 2b or 3 flow was restored in 80% of patients (32 of 40). At 90 days, 55% of patients (22 of 40) were functionally independent (modified Rankin score ≤2). In-hospital mortality was 13% (5 of 40). Symptomatic intracranial hemorrhage occurred in 15% of patients (6 of 40). Major vascular complications occurred in 5% of patients (2 of 40). ConclusionsMT can be successfully performed by interventional cardiologists with carotid stenting experience working closely with neurologists in hospitals lacking formally trained neurointerventionists. This model has the potential to increase access to timely care for patients with acute ischemic stroke.

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury.

Spinal cord injury (SCI) is a serious condition that affects bodily function; however, there is no effective therapy in clinical practice. MCC950, a selective NOD-like receptor protein-3 (NLRP3) inflammasome inhibitor, has been reported to alleviate canonical and non-canonical NLRP3 inflammasome activation of the inflammatory response in vitro and in vivo. However, the effect of MCC950 treatment on neurological post-SCI recovery remains unclear. In this study, we assessed the pharmacological effect of MCC950 on an experimental SCI model in vivo and neuronal injury in vitro. We found that MCC950 improved the grip strength, hind limb movements, spinal cord edema, and pathological injury in the SCI mice. We demonstrated that it exerted this effect by blocking NLRP3 inflammasome assembly, including NLRP3-ASC and NLRP3-Caspase-1 complexes, as well as the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-18. Moreover, we found that MCC950 reduced spinal neuron injury and NLRP3 inflammasome activation, which had been induced by oxygen–glucose deprivation (OGD) or lipopolysaccharides (LPS) in vitro. In conclusion, our findings indicate that MCC950 alleviates inflammatory response and improves functional recovery in the acute mice model of SCI by blocking NLRP3 inflammasome assembly and alleviating downstream neuroinflammation. Therefore, these findings could prove useful in the development of effective therapeutic strategies for the treatment and prognosis of SCI.

Protection against acute cerebral ischemia/reperfusion injury by QiShenYiQi via neuroinflammatory network mobilization

Cerebral ischemia/reperfusion injury (CI/RI) is a common feature of ischemic stroke, involving a period of impaired blood supply to the brain, followed by the restoration of cerebral perfusion through medical intervention. Although ischemia and reperfusion brain damage is a complex pathological process with an unclear physiological mechanism, more attention is currently focused on the neuroinflammatory response of an ischemia/reperfusion origin, and anti-inflammatory appears to be a potential therapeutic strategy following ischemic stroke. QiShenYiQi (QSYQ), a component-based Chinese medicine with Qi-tonifying and blood-activating property, has pharmacological actions of anti-inflammatory, antioxidant, mitochondrial protectant, anti-apoptosis, and antiplatelet aggregation. We have previously reported that the cardioprotective effect of QSYQ against ischemia/reperfusion injury is via improvement of mitochondrial functional integrity. In this research work, we aimed to investigate the possible mechanism involved in the neuroprotection of QSYQ in mice model of cerebral ischemia/reperfusion injury based on the inflammatory pathway. The cerebral protection was evaluated in the stroke mice after 24 h reperfusion by assessing the neurological deficit, cerebral infarction, brain edema, BBB functionality, and via histopathological assessment. TCM-based network pharmacology method was performed to establish and analyze compound-target-disease & function-pathway network so as to find the possible mechanism linking to the role of QSYQ in CI/RI. In addition, RT-qPCR was used to verify the accuracy of predicted signaling gene expression. As a result, improvement of neurological outcome, reduction of infarct volume and brain edema, a decrease in BBB disruption, and amelioration of histopathological alteration were observed in mice pretreated with QSYQ after experimental stroke surgery. Network pharmacology analysis revealed neuroinflammatory response was associated with the action of QSYQ in CI/RI. RT-qPCR data showed that the mice pretreated with QSYQ could significantly decrease IFNG-γ, IL-6, TNF-α, NF-κB p65, and TLR-4 mRNA levels and increase TGF-β1 mRNA level in the brain compared to the untreated mice after CI/RI (p < 0.05). In conclusion, our study indicated the cerebral protective effect of pretreatment with QSYQ against CI/RI, which may be partly related to its potential to the reduction of neuroinflammatory response in a stroke subject.

Abstract WP135: Engineered Exosomes With Elevated Mir-27a Improve Neurological Outcome in Ischemic Mice

Background: Augmentation of axonal growth enhances improvement of neurological function after stroke. Our previous in vitro study demonstrated that miR-27a promotes axonal growth of embryonic neurons. The present in vivo study investigated whether exosomes carrying elevated miR-27a (27a-exos) enhance axonal growth and neurological outcome after stroke. Methods and Results: The 27a-exos were isolated from medium of mesenchymal stromal cells (MSCs) transfected with lenti-miR-27 vector. In order to investigate axonal growth and underlying mechanisms, Emx1-Thy1-YFP mice with selective expression of yellow fluorescent protein (YFP) in pyramidal neurons were subjected to the permanent middle cerebral artery occlusion (MCAO). Quantitative RT-PCR analysis showed that compared with exosomes derived from empty-vector transfected MSCs (empty-exos), 27a-exos had 3.7 fold increased miR-27a. 27a-exos (3x10 11 particles) were injected intravenously into mice at 24h after MCAO. Compared with control mice, the empty-exos (n=7) significantly (p&lt;0.05) reduced the foot-fault (5±0.1 vs 11±0.5 in control) and the times to remove adhesive paper (seconds, 47±3 vs 70±4). However, compared with empty-exos, 27a-exos (n=7) further significantly (p&lt;0.05) reduced foot-fault (3.0±0.2) and times to remove the paper (38±1.7). Histopathological and in situ hybridization analysis showed that 27a-exos localized to neurons and significantly (p&lt;0.05) increased miR-27a in Emx1-YFP+ neurons (4±0.7 vs 1 in empty-exos), and augmented (p&lt;0.05) the density of YFP+/pNFH+ axons (7±2 vs 1 in empty-exos). Moreover, 27a-exos substantially decreased the levels of the inhibitory protein Sema6a in the YFP+ axons in peri-infarct areas. Conclusion: Our data suggest that tailored 27a-exos augment the therapeutic effect of exosomes on stroke recovery and that suppression of axonal inhibitory proteins such as Sema6a may contribute to the 27a-exo-enhanced axonal outgrowth to promote neurological recovery post stroke.

Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling.

Peroxynitrite (ONOO-) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO- in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO- could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO- production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO- production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO-/HMGB1/TLR2 signaling cascades.