Acute Phase Of Ischemic Stroke Research Articles

ESO guideline for the management of extracranial and intracranial artery dissection.

The aim of the present European Stroke Organisation guideline is to provide clinically useful evidence-based recommendations on the management of extracranial artery dissection (EAD) and intracranial artery dissection (IAD). EAD and IAD represent leading causes of stroke in the young, but are uncommon in the general population, thus making it challenging to conduct clinical trials and large observational studies. The guidelines were prepared following the Standard Operational Procedure for European Stroke Organisation guidelines and according to GRADE methodology. Our four recommendations result from a thorough analysis of the literature comprising two randomized controlled trials (RCTs) comparing anticoagulants to antiplatelets in the acute phase of ischemic stroke and twenty-six comparative observational studies. In EAD patients with acute ischemic stroke, we recommend using intravenous thrombolysis (IVT) with alteplase within 4.5 hours of onset if standard inclusion/exclusion criteria are met, and mechanical thrombectomy in patients with large vessel occlusion of the anterior circulation. We further recommend early endovascular or surgical intervention for IAD patients with subarachnoid hemorrhage (SAH). Based on evidence from two phase 2 RCTs that have shown no difference between the benefits and risks of anticoagulants versus antiplatelets in the acute phase of symptomatic EAD, we strongly recommend that clinicians can prescribe either option. In post-acute EAD patients with residual stenosis or dissecting aneurysms and in symptomatic IAD patients with an intracranial dissecting aneurysm and isolated headache, there is insufficient data to provide a recommendation on the benefits and risks of endovascular/surgical treatment. Finally, nine expert consensus statements, adopted by 8 to 11 of the 11 experts involved, propose guidance for clinicians when the quality of evidence was too low to provide recommendations. Some of these pertain to the management of IAD (use of IVT, endovascular treatment, and antiplatelets versus anticoagulation in IAD with ischemic stroke and use of endovascular or surgical interventions for IAD with headache only). Other expert consensus statements address the use of direct anticoagulants and dual antiplatelet therapy in EAD-related cerebral ischemia, endovascular treatment of the EAD/IAD lesion, and multidisciplinary assessment of the best therapeutic approaches in specific situations.

Efficacy and safety of carotid endarterectomy in the acute phase of ischemic stroke

Introduction.Nowadays it’s recommended to perform carotid endarterectomy (CEA) in up to 14 days after nondisabling stroke; the procedure is aimed at the prevention of recurrent stroke.The objectiveof this research was the comparison of short-term and long-term (12 months) outcomes with early (in up to 30 days) and delayed (30-180 days) CEA in patients who suffered strokes of various severities.Materials and methods. The research involved 88 patients who underwent CEA in the early stage (Group 1) and 88 patients who underwent CEA in their late period (Group 2). We assessed primary endpoints: ipsilateral stroke, myocardial infarction, 30-day Lethality, 30-day lethality after the surgery, any stroke or infarction (MACE). Secondary endpoints: the same parameters within 12 months after the surgery, post-surgery local or systemic complications, restenosis, changes in neurologic or cognitive status.Results.In 30 days we observed ipsilateral strokes in 3 patients in Group 1 (3.4 percent), it was lethal in 1 patient (1.1 percent). 170 of 176 (96 percent) patients were followed up for 12 months. One lethal stroke was registered in the group of late interventions (1.1 percent). No statistically significant differences were observed between the outcomes in early and late treatment groups. The severity of disability (mRS) in patients of the early intervention group was significantly smaller at discharge and in 12 months after surgery.Conclusion.The advisability of early CEA performance was proven by the absence of differences in post-surgery 30-day and longterm lethality as well as the progress of stroke or infarction with early or late CEA. In 12 months after the surgeries, significant improvement in neurologic status by mRS was only observed in the group of early interventions.

Neuronal CD200 Signaling Is Protective in the Acute Phase of Ischemic Stroke

CD200 (cluster of differentiation 200), a highly glycosylated protein primarily expressed on neurons in the central nervous system, binds with its receptor CD200R to form an endogenous inhibitory signal against immune responses. However, little is known about the effect of neuronal CD200 signaling in cerebral ischemia. The aim of this study was to investigate how neuronal CD200 signaling impacts poststroke inflammation and the ischemic injury. CD200 tma1lf/fl:Thy1CreER mice were treated with tamoxifen to induce conditional gene knockout (ICKO) of neuronal CD200. The mice were subjected to a 60-minute transient middle cerebral artery occlusion. Stroke outcomes, apoptotic cell death, immune cell infiltration, microglia activation, and other inflammatory profiles were evaluated at 3 and 7 days after stroke. Infarct volumes were significantly larger, and behavioral deficits more severe in ICKO versus control mice at 3 days after middle cerebral artery occlusion. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay also revealed a significant increase in apoptotic neuronal death in CD200 ICKO mice. An enhancement in lymphocytic infiltration and microglial proinflammatory responses were revealed by flow cytometry at 3 and 7 days after stroke in ICKO mice, accompanied by an increased microglial phagocytosis activity. Plasma proinflammatory cytokine (TNFα [tumor necrosis factor alpha] and IL [interleukin]-1β) levels significantly increased at 3 days, and IL-1β/IL-6 levels increased at 7 days in ICKO versus control animals. ICKO led to significantly lower baseline level of CD200 both in brain and plasma. Neuronal CD200 inhibits proinflammatory responses and is protective against stroke injury.

Characteristics, comorbidities, and outcomes of acute ischemic stroke cases treated with thrombolysis in Sanglah General Hospital Bali: A case series

Background: Intravenous recombinant tissue plasminogen activator (IV rt-PA) in eligible patient groups is the main therapy for acute phase ischemic stroke within 4.5 hours of symptom onset which can significantly improve functional outcome. However, not all patients who underwent thrombolysis had a good outcome. Case: We report a series of seven patients cases undergoing IV thrombolysis from 2019-2020 at Sanglah General Hospital with varying baseline conditions and outcomes. Most cases benefit from IV rt-PA administration. There was one case with a poor outcome and one case with a rare anaphylactic reaction following alteplase administration. Conclusion: The number of thrombolysis procedure which is the main treatment of acute ischemic stroke is quite small. It is necessary to increase public education and understanding regarding the rapid response to acute stroke symptoms. Most of the cases yielded good outcomes while several cases had unfavorable outcomes related to variable factors. Hemorrhagic transformation does not directly associate with poor outcome. Clinicians also need to increase awareness of allergic reactions risk to rt-PA and provide prompt treatment.

Age-Dependent Association Between Elevated Homocysteine and Cognitive Impairment in a Post-stroke Population: A Prospective Study.

Background and Purpose: The results regarding the independent association between homocysteine (Hcy) levels and post-stroke cognitive impairment (PSCI) were inconsistent. The effect of age on this association has yet to be explored. This study aims to determine the relationship between Hcy levels, age, and cognitive impairment in a post-stroke population.Methods: A total of 592 patients with acute ischemic stroke (AIS) completed follow-up. Serum Hcy levels were measured enzymatically by spectrophotometry within 24 h of admission. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE) 1 month after stroke, and the scores ≤ 24 were considered as cognitive impairment. Our study was dichotomized into two groups by a cut-off of 65 years. Multivariate logistic regression models were used to determine the association between baseline Hcy levels and cognitive impairment.Results: According to the MMSE score, 317 (53.5%) patients had cognitive impairment. Patients with higher levels of Hcy were more prone to have cognitive impairment 1 month after stroke than patients with lower levels of Hcy (p < 0.001). The optimal cut-off points of Hcy level (μmol/L) were (T1) ≤ 8, (T2) 8–12, and (T3) ≥ 12. After adjusting for confounding factors, the multivariate regression analysis showed that the third Hcy tertile was independently associated with cognitive impairment [odds ratio (OR) = 2.057, 95% confidence interval (CI) = 1.133–3.735, p = 0.018). A stronger association [T2 (OR = 2.266, 95% CI = 1.042–4.926, p = 0.039); T3 (OR =3.583, 95% CI = 1.456–8.818, p = 0.005)] was found in the younger group. However, the independent association was not confirmed in the older group.Conclusions: Elevated Hcy levels in the acute phase of ischemic stroke were independently associated with cognitive impairment in a post-stroke population. Furthermore, the association was age-dependent and more meaningful in a younger population aged below 65. So, Hcy levels in patients with stroke should be well-monitored, especially in younger patients.

Natural Killer Cells Are Present in Rag1\u2212/\u2212 Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

Rag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

English

BACKGROUND Disturbance of brain iron homeostasis have been linked to acute neuronal injury following cerebral ischemia. Increased body iron stores measured as serum ferritin is an acute-phase reactant involved in cellular defence against oxidative stress and it constitutes the main intracellular iron storage protein. In a healthy population, iron excess may not be a major concern; however, in persons with high oxidative stress and dyslipidaemia, iron excess may place them at greater risk. Hence this study is undertaken to find out the role of iron in acute ischemic stroke and to estimate the iron stores, measured as serum ferritin in acute ischemic stroke patients. METHODS A minimum of 180 consecutive patients above 40 years in the acute phase of ischemic stroke within 72 hours of first episode admitted to the neurology department was selected for the study. Data collection was based on Interview method by detailed questionnaire and laboratory investigations. Quantitative determination of serum ferritin was done by immunoenzymatic colorimetric method using ELISA technique. Association of risk factors like age, gender, place of residence, history of hypertension, dyslipidaemia and diabetes between cases with elevated ferritin and normal values were analysed. RESULTS In the present study incidence of stroke was more common among patients with the age group of more than 50 years and among the 180 cases, 75 % showed elevated serum ferritin levels. Association of risk factors between cases with elevated ferritin and cases with normal ferritin were studied and it shown that history of hypertension, dyslipidaemia and diabetes were statistically significant. Multiple logistic regression showed history of hypertension and dyslipidaemia that were independent predictors of elevated ferritin levels among stroke patients. CONCLUSIONS Serum Ferritin was increased in acute ischemic stroke patients. There was significant association of factors like history of hypertension, dyslipidaemia and diabetes with elevated ferritin levels. KEYWORDS Stroke, Ferritin, Oxidative Stress, Free Radicals

Stroke occurrence in patients with STEMI: does BNP help to predict?

Abstract Funding Acknowledgements Type of funding sources: None. OnBehalf Portuguese Registry of Acute Coronary Syndromes (ProACS) Introduction Although brain natriuretic peptides (BNP) has been primarily identified in brain tissue, its clinical application is primarily related to cardiac disease, namely heart failure. The current information on this natriuretic peptide in cerebrovascular disease is limited, however some studies performed showed an acute elevation of BNP during the acute phase of ischemic stroke. Objective Evaluation of prognostic value of BNP in the occurrence of in-hospital ischemic stroke in patients admitted with ST elevation myocardial infarction (STEMI). Material and methods Retrospective analysis of patients´ data admitted with STEMI at multicentric registry between October 2010 and January 2019. Patients were divided into two groups: group 1 – patients who suffered an ischemic stroke (0.8%) and group 2 – without stroke (99.2%). Demographic and clinical characteristics were compared. A logistic regression was performed to evaluate prognostic value of BNP in the occurrence of in-hospital stroke and cardiovascular events. Results Admitted 1650 patients with STEMI. There was no statistically significant difference between mean age in both groups (mean age 64 ± 13 years, p 0.122) and most patients were male (75.4%). A higher percentage of group 1 patients had a previous diagnosis of stroke/ transitory ischemic accident (28.6 vs 5.4%, p 0.006) but there was no significant differences regarding the percentages of previous arterial hypertension, diabetes, dyslipidaemia neither peripheral vascular disease. Mean values of BNP at admission were higher in group 1: 839 ± 1088 vs 333 ± 639 pg/ml (p 0.04). All patients were submitted to coronary angiography, without evidence of significant differences regarding severity of coronary disease. In group 1 patients mean left ventricle ejection fraction (LVEF) during hospitalization was lower: 43 ± 11 vs 53 ± 13 %, p 0.005. Logistic regression identified as prognostic factors of in-hospital ischemic stroke: previous stroke/ transitory ischemic accident (p 0.007), dementia (p 0.005) or thoracic pain at STEMI presentation (p 0.005). Although patients with higher levels of BNP had suffered more stroke (0.5% in group with BNP &amp;lt; 100pg/ml; 0.6% in group with 100 ≤ BNP &amp;lt; 400 pg/ml; and 2.0% in group with BNP ≥ 400 pg/ml), BNP did not show to be predictor of stroke occurrence in this context (p 0.862). Conclusion Although patients with higher levels of BNP had suffered more stroke, BNP did not show to be predictor of stroke occurrence in patients admitted with STEMI.

Effects of double-dose statin therapy for the prevention of post-stroke epilepsy: A prospective clinical study

BackgroundTo determine treatment effects on the incidence of post-stroke epilepsy (PSE) using different doses of statin, a prospective hospital-based cohort study was designed to explore whether a double-dose statin treatment can better prevent the occurrence of PSE. MethodsA total of 1152 patients with newly diagnosed ischemic stroke admitted to our hospital from March to August 2017 were selected, 1033 of whom were followed-up. Patients were divided into two treatment groups:(1) standard-dose (20 mg atorvastatin or 10 mg rosuvastatin,daily oral; 788 patients); and (2) double-dose (40 mg atorvastatin or 20 mg rosuvastatin, daily oral; 245 patients).At 18 months follow-up was conducted to compare the incidence of PSE between groups. ResultsIn general, in the standard-dose group we observed two cases of early seizure (ES) (0.25%), 22 cases oflate seizure (LS) (2.79%) and 20 cases of PSE (2.54%). In the double-dose group, onepatient had ES (0.41%), two patients had LS (0.82%), and onepatient had PSE (0.41%). The incidence of PSE was significantly lower in the double-dose group as compared to the standard-dose group. There was a higher proportion of PSE in patients younger than 65 years and in males. Three patients had ES; one presented with focal aware seizure (FAS), and two had focal to bilateral tonic-clonic seizure (FBTCS). Among the 21 patients with PSE, there were two cases of FAS, five cases of focal impaired awareness seizure (FIAS), five cases of FBTCS, and nine cases of GTCS, suggesting that partial seizure is the most common type of PSE. Cerebral cortex was involved in 85.75% of cases with PSE, and multiple lobes were involved in 61.9% of cases with PSE. ConclusionIncreasing the dose of statin treatment during the acute phase of ischemic stroke reduces the incidence of PSE. Further research is needed to understand the mechanisms underlying the potential preventative effects of statins against PSE.

Etiological structure and comorbidity of cardioembolic stroke

Objective. Cardioembolic (CE) subtype has recently become increasingly important in the structure of brain stroke. This raises the question about the causes of CE stroke at the present stage. Clinical experience shows that the presence of comorbid disorders has a great influence on the course, early diagnosis, therapy and prognosis of the disease. However, the data on the structure of CE stroke and comorbid disorders are contradictory. This article aimed at studying etiological structure of CE stroke and its comorbidities.Design and methods. The study included 62 patients at the acute phase of ischemic stroke aged from 44 to 96 years. The CHA2DS2-VASc scale was used to evaluate the expected annual stroke risk. Results. Our data show that the etiological structure of the CE stroke is presented predominantly by atrial fibrillation, followed by acute myocardial infarction. Compared to atherothrombotic stroke, the CE stroke was found to have a higher comorbidity index. CHA2DS2-VASc total score in patients with CE stroke showed a high risk of recurrent acute cerebrovascular accident.Conclusions. Thus, an interdisciplinary approach to the diagnostic and treatment process involving a cardiologist and neurologist is required in order to improve the effectiveness of therapy and prognosis.

Autonomic dysregulation in acute ischemic stroke patient with insomnia

ObjectiveThis study aimed to assess autonomic dysregulation by measuring Heart Rate Variability (HRV) parameters in acute ischemic stroke patients with insomnia. MethodsThis was a descriptive observational study on 5 participants (4 females and one male) with acute ischemic stroke and insomnia. All participants were assessed through the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) and then tested using a Polar H10 device for 5min recording during night sleep. The collected data analyzed by Kubios HRV Analysis Software 3.2 (MATLAB, Kuopio, Finland). ResultsThis study showed that all participants (age 51.2±12.61) had subthreshold to moderate insomnia based on ISI (14.8±2.48) and had poor sleep quality based on PSQI (16.4±3.72). There was an increase of mean heart rate (HR) (81.8±13.86), root mean square of successive differences (rMSSD) (46.6±38.05), and sympathetic nervous system index (SNS Index) (1.542±1.567), as well as the decrease of standard deviation of normal-normal interval (SDNN) (37.8±20.53), low frequency (LF) (449.2±371.8), high frequency (HF) (812.6±773.8), LF/HF (1.89±1.72), and parasympathetic nervous system index (PNS Index) (−0.462±1.210). ConclusionsThe Analysis of HRV showed an autonomic dysregulation in the form of parasympathetic dysfunction and sympathetic hyperactivation during night sleep in the acute phase of ischemic stroke with insomnia.

Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies

Ischemic stroke (IS) remains one of the major causes of death and disability due to the limited ability of central nervous system cells to regenerate and differentiate. Although several advances have been made in stroke therapies in the last decades, there are only a few approaches available to improve IS outcome. In the acute phase of IS, mechanical thrombectomy and the administration of tissue plasminogen activator have been widely used, while aspirin or clopidogrel represents the main therapy used in the subacute or chronic phase. However, in most cases, stroke patients fail to achieve satisfactory functional recovery under the treatments mentioned above. Recently, cell therapy, especially stem cell therapy, has been considered as a novel and potential therapeutic strategy to improve stroke outcome through mechanisms, including cell differentiation, cell replacement, immunomodulation, neural circuit reconstruction, and protective factor release. Different stem cell types, such as mesenchymal stem cells, marrow mononuclear cells, and neural stem cells, have also been considered for stroke therapy. In recent years, many clinical and preclinical studies on cell therapy have been carried out, and numerous results have shown that cell therapy has bright prospects in the treatment of stroke. However, some cell therapy issues are not yet fully understood, such as its optimal parameters including cell type choice, cell doses, and injection routes; therefore, a closer relationship between basic and clinical research is needed. In this review, the role of cell therapy in stroke treatment and its mechanisms was summarized, as well as the function of different stem cell types in stroke treatment and the clinical trials using stem cell therapy to cure stroke, to reveal future insights on stroke-related cell therapy, and to guide further studies.

TMAO Aggregates Neurological Damage Following Ischemic Stroke by Promoting Reactive Astrocytosis and Glial Scar Formation via the Smurf2/ALK5 Axis.

Ischemic stroke has been reported to cause significant changes to memory, thinking, and behavior. Intriguingly, recently reported studies have indicated the association of Trimethylamine N-oxide (TMAO) with the acute phase of ischemic stroke. However, the comprehensive underlying mechanism remained unknown. The objective of the present study was to investigate the association between TMAO and recovery of neurological function after ischemic stroke. For this purpose, a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established and treated with TMAO or/and sh-ALK5, followed by the neurological function evaluation. Behaviors of rats were observed through staircase and cylinder tests. Moreover, the expression of Smurf2 and ALK5 was detected by immunohistochemistry while expression of GFAP, Neurocan, and Phosphacan in brain tissues was determined by immunofluorescence. Thereafter, gain- and loss-of-function assays in astrocytes, the proliferation, viability, and migration were evaluated by the EdU, CCK-8, and Transwell assays. Besides, Smurf2 mRNA expression was determined by the RT-qPCR, whereas, Smurf2, ALK5, GFAP, Neurocan, and Phosphacan expression was evaluated by the Western blotting. Finally, the interaction of Smurf2 with ALK5 and ALK5 ubiquitination was assessed by the co-immunoprecipitation. Notably, our results showed that TMAO promoted the proliferation of reactive astrocyte and formation of glial scar in MCAO/R rats. However, this effect was abolished by the Smurf2 overexpression or ALK5 silencing. We further found that TMAO upregulated the ALK5 expression by inhibiting the ubiquitination role of Smurf2. Overexpression of ALK5 reversed the inhibitory effect of Smurf2 on astrocyte proliferation, migration, and viability. Collectively, our work identifies the evolutionarily TMAO/Smurf2/ALK5 signaling as a major genetic factor in the control of reactive astrocyte proliferation and glial scar formation in ischemic stroke, thus laying a theoretical foundation for the identification of ischemic stroke.

Abstract P9: Mid-Regional Pro-Adrenomedullin as a Novel Biomarker of Transient Ischemic Attack

Background: Transient ischemic attack (TIA) is often a warning sign for ischemic stroke within a couple of months and should be treated as an emergency disease. However, the symptoms often disappear within a few hours, making the diagnosis of TIA difficult. The peptide hormone adrenomedullin (AM) increases during the acute phase of ischemic stroke because AM is produced by vascular endothelial cells as a biological defense mechanism against hypoxia and oxidative stress during cerebral ischemia. Therefore, we hypothesized that the blood levels of mid-regional pro-adrenomedullin (MR-pro-AM), half-life of which is several hours and much longer than AM, in patients with TIA could be a useful biomarker for the diagnosis of TIA. Method: We retrospectively compared the blood levels of MR-pro-AM using stored peripheral blood samples of the TIA cohort within 14 days from onset in the National Cerebral and Cardiovascular Center from April 1, 2016 to March 30, 2019, and those of the population-based cohort of the Kyoto Prefectural University of Medicine. Results: The TIA cohort (n = 39) was significantly older (73 vs. 58 years old) and showed higher frequency of cerebrovascular risk factors and higher levels of MR-pro-AM (0.584 vs. 0.418 nmol/l) than the population-based cohort (n = 1298). The MR-pro-AM level was significantly associated with TIA: odds ratio (OR) per 0.1 nmol/l MR-pro-AM increment was 2.8 (95% confidence interval (CI) = 2.2-3.6) in univariable analysis and 1.5 (95% CI = 1.1-2.1) in multivariable analysis with sex, age, chronic kidney disease and cerebrovascular risk factors as covariates. The cutoff value of MR-pro-AM was 0.523 nmol/l based on receiver operating characteristic curve analysis for TIA, with a sensitivity of 69% and a specificity of 88% (area under the curve = 0.78). Moreover, the model with the blood level of MR-pro-AM in addition to the prediction model the ABCD 2 score predicted TIA more accurately (net reclassification improvement = 1.14, p &lt; 0.001). The MR-pro-AM level was found significantly higher in the TIA cohort than the population-based cohort after propensity score-matching (0.665 vs. 0.525 nmol/l, p = 0.047). Conclusion: MR-pro-AM may be a promising diagnostic biomarker for TIA.

Combined therapy of intensive statin plus intravenous rt-PA in acute ischemic stroke: the INSPIRE randomized clinical trial.

To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy. A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20mg daily × 14days) and the control group (rosuvastatin 5mg daily × 14days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90days. The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran-Mantel-Haenszel test). The incidence of primary safety endpoint events (sICH) in 90days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999). The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile. URL: http://www.chictr.org . Unique identifier: ChiCTR-IPR-16008642.

Single- and two- chain tissue type plasminogen activator treatments differentially influence cerebral recovery after stroke

Tissue type Plasminogen Activator (tPA), named alteplase (Actilyse®) under its commercial form, is currently the only pharmacological treatment approved during the acute phase of ischemic stroke, used either alone or combined with thrombectomy. Interestingly, the commercial recombinant tPA (rtPA) contains two physiological forms of rtPA: the single chain rtPA (sc-rtPA) and the two-chains rtPA (tc-rtPA), with differential properties demonstrated in vitro. Using a relevant mouse model of thromboembolic stroke, we have investigated the overall effects of these two forms of rtPA when infused early after stroke onset (i.e. 20 min) on recanalization, lesion volumes, alterations of the integrity of the blood brain barrier and functional recovery. Our data reveal that there is no difference in the capacity of sc-rtPA and tc-rtPA to promote fibrinolysis and reperfusion of the tissue. However, compared to sc-rtPA, tc-rtPA is less efficient to reduce lesion volumes and to improve functional recovery, and is associated with an increased opening of the blood brain barrier. These data indicate better understanding of differential effects of these tPA forms might be important to ultimately improve stroke treatment.

DL-3n-Butylphthalide Improves Blood-Brain Barrier Integrity in Rat After Middle Cerebral Artery Occlusion.

Objective: DL-3n-butylphthalide (NBP) has beneficial effects in different stages of ischemic stroke. Our previous studies have demonstrated that NBP promoted angiogenesis in the perifocal region of the ischemic brain. However, the molecular mechanism of NBP for blood–brain barrier protection in acute ischemic stroke was unclear. Here, we explored the neuroprotective effects of NBP on blood–brain barrier integrity in the acute phase of ischemic stroke in a rat model.Methods: Adult male Sprague–Dawley rats (n = 82) underwent 2 h of transient middle cerebral artery occlusion and received 90 mg/kg of NBP for 3 days. Brain edema, infarct volume, surface blood flow, and neurological severity score were evaluated. Blood–brain barrier integrity was evaluated by Evans blue leakage and changes in tight junction proteins. We further examined AQP4 and eNOS expression, MMP-9 enzyme activity, and possible signaling pathways for the role of NBP after ischemic stroke.Results: NBP treatment significantly increased eNOS expression and surface blood flow in the brain, reduced brain edema and infarct volume, and improved neurological severity score compared to the control group (p < 0.05). Furthermore, NBP attenuated Evans blue and IgG leakage and increased tight junction protein expression compared to the control after 1 and 3 days of ischemic stroke (p < 0.05). Finally, NBP decreased AQP4 expression, MMP-9 enzyme activity, and increased MAPK expression during acute ischemic stroke.Conclusion: NBP protected blood–brain barrier integrity and attenuated brain injury in the acute phase of ischemic stroke by decreasing AQP4 expression and MMP-9 enzyme activity. The MAPK signaling pathway may be associated in this process.

Plasma soluble suppression of tumorigenicity 2 and depression after acute ischemic stroke.

Soluble suppression of tumorigenicity 2 (sST2) might be related to stroke and depression, but the association of sST2 with poststroke depression (PSD) is unclear. The study aimed to prospectively assess the association between plasma sST2 levels and PSD. A total of 635 acute ischemic stroke patients with sST2 measurements from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this analysis. We used the 24-item Hamilton Rating Scale for Depression to assess depression at 3months, and PSD was defined as a score of ≥8. Logistic regression analysis was performed to estimate the risk of PSD associated with sST2, and net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to assess the predictive value of sST2. Two hundred fifty (39.4%) patients developed depression at 3months after ischemic stroke. Patients with PSD had higher sST2 levels than patients without PSD (172.7 vs. 153.8pg/ml; p=0.003). After adjustment for age, sex, education, National Institutes of Health Stroke Scale score, and other covariates, the odds ratio for the highest quartile of sST2 compared with the lowest quartile was 1.84 (95% confidence interval, 1.10-3.08) for PSD. Adding sST2 to a conventional model notably improved risk prediction for PSD (category-free NRI=19.34%, 95% confidence interval=4.39%-34.28%, p=0.017; IDI=1.20%, 95% confidence interval=0.25%-2.15%, p=0.014). Increased plasma sST2 levels in the acute phase of ischemic stroke were significantly associated with the increased risk of PSD, independently of conventional risk factors.

Non-coding RNAs and other determinants of neuroinflammation and endothelial dysfunction: regulation of gene expression in the acute phase of ischemic stroke and possible therapeutic applications.

Ischemic stroke occurs under a variety of clinical conditions and has different pathogeneses, resulting in necrosis of brain parenchyma. Stroke pathogenesis is characterized by neuroinflammation and endothelial dysfunction. Some of the main processes triggered in the early stages of ischemic damage are the rapid activation of resident inflammatory cells (microglia, astrocytes and endothelial cells), inflammatory cytokines, and translocation of intercellular nuclear factors. Inflammation in stroke includes all the processes mentioned above, and it consists of either protective or detrimental effects concerning the “polarization” of these processes. This polarization comes out from the interaction of all the molecular pathways that regulate genome expression: the epigenetic factors. In recent years, new regulation mechanisms have been cleared, and these include non-coding RNAs, adenosine receptors, and the activity of mesenchymal stem/stromal cells and microglia. We reviewed how long non-coding RNA and microRNA have emerged as an essential mediator of some neurological diseases. We also clarified that their roles in cerebral ischemic injury may provide novel targets for the treatment of ischemic stroke. To date, we do not have adequate tools to control pathophysiological processes associated with stroke. Our goal is to review the role of non-coding RNAs and innate immune cells (such as microglia and mesenchymal stem/stromal cells) and the possible therapeutic effects of their modulation in patients with acute ischemic stroke. A better understanding of the mechanisms that influence the “polarization” of the inflammatory response after the acute event seems to be the way to change the natural history of the disease.

Timing is everything: Exercise therapy and remote ischemic conditioning for acute ischemic stroke patients.

Physical exercise is a promising rehabilitative strategy for acute ischemic stroke. Preclinical trials suggest that exercise restores cerebral blood circulation and re-establishes the blood–brain barrier’s integrity with neurological function and motor skill improvement. Clinical trials demonstrated that exercise improves prognosis and decreases complications after ischemic events. Due to these encouraging findings, early exercise rehabilitation has been quickly adopted into stroke rehabilitation guidelines. Unfortunately, preclinical trials have failed to warn us of an adverse effect. Trials with very early exercise rehabilitation (within 24 h of ischemic attack) found an inferior prognosis at 3 months. It was not immediately clear as to why exercise was detrimental when performed very early while it was ameliorative just a few short days later. This review aimed to explore the potential mechanisms of harm seen in very early exercise administered to acute ischemic stroke patients. To begin, the mechanisms of exercise’s benefit were transposed onto the current understanding of acute ischemic stroke’s pathogenesis, specifically during the acute and subacute phases. Then, exercise rehabilitation’s mechanisms were compared to that of remote ischemic conditioning (RIC). This comparison may reveal how RIC may be providing clinical benefit during the acute phase of ischemic stroke when exercise proved to be harmful.