scholarly journals MiR-29a Knockout Aggravates Neurological Damage by Pre-polarizing M1 Microglia in Experimental Rat Models of Acute Stroke

2021 ◽  
Vol 12 ◽  
Author(s):  
Fangfang Zhao ◽  
Haiping Zhao ◽  
Junfen Fan ◽  
Rongliang Wang ◽  
Ziping Han ◽  
...  

ObjectiveBy exploring the effects of miR-29a-5p knockout on neurological damage after acute ischemic stroke, we aim to deepen understanding of the molecular mechanisms of post-ischemic injury and thus provide new ideas for the treatment of ischemic brain injury.MethodsmiR-29a-5p knockout rats and wild-type SD rats were subjected to transient middle cerebral artery occlusion (MCAO). miR-29a levels in plasma, cortex, and basal ganglia of ischemic rats, and in plasma and neutrophils of ischemic stroke patients, as well as hypoxic glial cells were detected by real-time PCR. The infarct volume was detected by TTC staining and the activation of astrocytes and microglia was detected by western blotting.ResultsThe expression of miR-29a-5p was decreased in parallel in blood and brain tissue of rat MCAO models. Besides, miR-29a-5p levels were reduced in the peripheral blood of acute stroke patients. Knockout of miR-29a enhanced infarct volume of the MCAO rat model, and miR-29a knockout showed M1 polarization of microglia in the MCAO rat brain. miR-29a knockout in rats after MCAO promoted astrocyte proliferation and increased glutamate release.ConclusionKnockout of miR-29a in rats promoted M1 microglial polarization and increased glutamate release, thereby aggravating neurological damage in experimental stroke rat models.

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniel Omileke ◽  
Sara Azarpeykan ◽  
Steven W. Bothwell ◽  
Debbie Pepperall ◽  
Daniel J. Beard ◽  
...  

AbstractReperfusion therapies re-establish blood flow after arterial occlusion and improve outcome for ischaemic stroke patients. Intracranial pressure (ICP) elevation occurs 18–24 h after experimental stroke. This elevation is prevented by short-duration hypothermia spanning the time of reperfusion. We aimed to determine whether hypothermia-rewarming completed prior to reperfusion, also prevents ICP elevation 24 h post-stroke. Transient middle cerebral artery occlusion was performed on male outbred Wistar rats. Sixty-minute hypothermia to 33 °C, followed by rewarming was induced prior to reperfusion in one group, and after reperfusion in another group. Normothermia controls received identical anaesthesia protocols. ΔICP from pre-stroke to 24 h post-stroke was measured, and infarct volumes were calculated. Rewarming pre-reperfusion prevented ICP elevation (ΔICP = 0.3 ± 3.9 mmHg vs. normothermia ΔICP = 5.2 ± 2.1 mmHg, p = 0.02) and reduced infarct volume (pre-reperfusion = 78.6 ± 23.7 mm3 vs. normothermia = 125.1 ± 44.3 mm3, p = 0.04) 24 h post-stroke. There were no significant differences in ΔICP or infarct volumes between hypothermia groups rewarmed pre- or post-reperfusion. Hypothermia during reperfusion is not necessary for prevention of ICP rise or infarct volume reduction. Short-duration hypothermia may be an applicable early treatment strategy for stroke patients prior to- during-, and after reperfusion therapy.


2021 ◽  
Author(s):  
Daniel Omileke ◽  
Sara Azarpeykan ◽  
Steven W Bothwell ◽  
Debbie Pepperall ◽  
Daniel J Beard ◽  
...  

Abstract Reperfusion therapies re-establish blood flow after arterial occlusion and improve outcome for ischaemic stroke patients. Intracranial pressure (ICP) elevation occurs 18–24 h after experimental stroke. This elevation is prevented by short-duration hypothermia spanning the time of reperfusion. We aimed to determine whether hypothermia-rewarming completed prior to reperfusion, also prevents ICP elevation 24 h post-stroke. Transient middle cerebral artery occlusion was performed on male outbred Wistar rats. Sixty-minute hypothermia to 33℃, followed by rewarming was induced prior to reperfusion in one group, and after reperfusion in another group. Normothermia controls received identical anaesthesia protocols. ΔICP from pre-stroke to 24 h post-stroke was measured, and infarct volumes were calculated. Rewarming pre-reperfusion prevented ICP elevation (ΔICP = 0.3 ± 3.9 mmHg vs. normothermia ΔICP = 5.2 ± 2.1 mmHg, p = 0.02) and reduced infarct volume (pre-reperfusion = 78.6 ± 23.7 mm3 vs. normothermia = 125.1 ± 44.3 mm3, p = 0.04) 24 h post-stroke. There were no significant differences in ΔICP or infarct volumes between hypothermia groups rewarmed pre-or post-reperfusion. Hypothermia during reperfusion is not necessary for prevention of ICP rise or infarct volume reduction. Short-duration hypothermia is a broadly applicable potential early treatment strategy for stroke patients prior to- during-, and after reperfusion therapy.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuejiao Li ◽  
Yankai Dong ◽  
Ye Ran ◽  
Yanan Zhang ◽  
Boyao Wu ◽  
...  

Abstract Background We show previously that three-dimensional (3D) spheroid cultured mesenchymal stem cells (MSCs) exhibit reduced cell size thus devoid of lung entrapment following intravenous (IV) infusion. In this study, we determined the therapeutic effect of 3D-cultured MSCs on ischemic stroke and investigated the mechanisms involved. Methods Rats underwent middle cerebral artery occlusion (MCAO) and reperfusion. 1 × 106 of 3D- or 2D-cultured MSCs, which were pre-labeled with GFP, were injected through the tail vain three and seven days after MCAO. Two days after infusion, MSC engraftment into the ischemic brain tissues was assessed by histological analysis for GFP-expressing cells, and infarct volume was determined by MRI. Microglia in the lesion were sorted and subjected to gene expressional analysis by RNA-seq. Results We found that infusion of 3D-cultured MSCs significantly reduced the infarct volume of the brain with increased engraftment of the cells into the ischemic tissue, compared to 2D-cultured MSCs. Accordingly, in the brain lesion of 3D MSC-treated animals, there were significantly reduced numbers of amoeboid microglia and decreased levels of proinflammatory cytokines, indicating attenuated activation of the microglia. RNA-seq of microglia derived from the lesions suggested that 3D-cultured MSCs decreased the response of microglia to the ischemic insult. Interestingly, we observed a decreased expression of mincle, a damage-associated molecular patterns (DAMPs) receptor, which induces the production of proinflammatory cytokines, suggestive of a potential mechanism in 3D MSC-mediated enhanced repair to ischemic stroke. Conclusions Our data indicate that 3D-cultured MSCs exhibit enhanced repair to ischemic stroke, probably through a suppression to ischemia-induced microglial activation.


2021 ◽  
pp. 0271678X2199298
Author(s):  
Chao Li ◽  
Chunyang Wang ◽  
Yi Zhang ◽  
Owais K Alsrouji ◽  
Alex B Chebl ◽  
...  

Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by ∼36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by ∼43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.


Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hannah J Irvine ◽  
Thomas W Battey ◽  
Ann-Christin Ostwaldt ◽  
Bruce C Campbell ◽  
Stephen M Davis ◽  
...  

Introduction: Revascularization is a robust therapy for acute ischemic stroke, but animal studies suggest that reperfusion edema may attenuate its beneficial effects. In stroke patients, early reperfusion consistently reduces infarct volume and improves long-term functional outcome, but there is little clinical data available regarding reperfusion edema. We sought to elucidate the relationship between reperfusion and brain edema in a patient cohort of moderate to severe stroke. Methods: Seventy-one patients enrolled in the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) with serial brain magnetic resonance imaging and perfusion-weighted imaging (PWI) were analyzed. Reperfusion percentage was calculated based on the difference in PWI lesion volume at baseline and follow-up (day 3-5). Midline shift (MLS) was measured on the day 3-5 fluid attenuated inversion recovery (FLAIR) sequence. Swelling volume and infarct growth volume were assessed using region-of-interest analysis on the baseline and follow-up DWI scans based on our prior methods. Results: Greater percentage of reperfusion was associated with less MLS (Spearman ρ = -0.46; P <0.0001) and reduced swelling volume (Spearman ρ = -0.56; P <0.0001). In multivariate analysis, reperfusion was an independent predictor of less MLS ( P <0.006) and decreased swelling volume ( P <0.0054), after adjusting for age, baseline NIHSS, admission blood glucose, baseline DWI volume, and IV tPA treatment. Conclusions: Reperfusion is associated with reduced brain edema as measured by MLS and swelling volume. While our data do not exclude the possibility of reperfusion edema in certain circumstances, in stroke patients, reperfusion following acute stroke is predominantly linked to less brain swelling.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Betty A McGee ◽  
Melissa Stephenson

Background and Purpose: Thrombolytic therapy is a key link in the stroke chain of survival. Data suggests that four components are vital in decreasing door to thrombolytic administration in acute stroke patients eligible for treatment. Analysis of system data, pre and post implementation of a Door to Needle Project, afforded the opportunity to assess. Hypothesis: We assessed the hypothesis that commitment, collaboration, communication, and consistency (referred to as Four C’s) are vital in improving door to thrombolytic administration time in ischemic stroke patients. Methods: In this quantitative study, we utilized case data collected by a quality improvement team serving five emergency departments within a healthcare system. We retrospectively reviewed times of thrombolytic administration from admission to the emergency department in acute ischemic stroke patients. Cases were included based on eligibility criteria from American Heart Association’s Get With the Guidelines. Times from 2019 were compared with times through April 2020, before and after implementation of the project, which had multidisciplinary process interventions that reinforced the Four C’s. Results: The data revealed a 13.5 % reduction in median administration time. Cases assessed from 2019 had a median time of 52 minutes from door to thrombolytic administration, 95% CI [47.0, 59.0], n = 52. Cases assessed through April 2020 had a median time of 45 minutes from door to thrombolytic administration, 95% CI [39.0, 57.5], n = 18. Comparing cases through April 2020 to those of 2019, there were improvements of 38.1% fewer cases for administration in greater than 60 minutes and 27.8% fewer cases for administration in greater than 45 minutes. Conclusion: The hypothesis that Four C’s are vital in improving door to thrombolytic administration was validated by a decrease in median administration time as well as a reduction in cases exceeding targeted administration times. The impact to clinical outcomes is significant as improving administration time directly impacts the amount of tissue saved. Ongoing initiatives encompassing the Four C’s, within a Cerebrovascular System of Care, are essential in optimizing outcomes in acute stroke patients.


Author(s):  
Amy K Starosciak ◽  
Italo Linfante ◽  
Gail Walker ◽  
Osama O Zaidat ◽  
Alicia C Castonguay ◽  
...  

Background: Recanalization of the occluded artery is a powerful predictor of good outcome in acute ischemic stroke secondary to large artery occlusions. Mechanical thrombectomy with stent-trievers results in higher recanalization rates and better outcomes compared to previous devices. However, despite successful recanalization rates (Treatment in Cerebral Infarction, TICI, score ≥ 2b) between 70 and 90%, good clinical outcomes assessed by modified Rankin Scale (mRS) ≤ 2 is present in 40-50% of patients . We aimed to evaluate predictors of poor outcomes (mRS > 2) despite successful recanalization (TICI ≥ 2b) in the acute stroke patients treated with the Solitaire device of the North American Solitaire Stent Retriever Acute Stroke (NASA) registry. Methods: The NASA registry is a multicenter, non-sponsored, physician-conducted, post-marketing registry on the use of SOLITAIRE FR device in 354 acute, large vessel, ischemic stroke patients. Logistic regression was used to evaluate patient characteristics and treatment parameters for association with 90-day mRS score of 0-2 (good outcome) versus 3-6 (poor outcome) within patients who were recanalized successfully (Thrombolysis in Cerebral Infarction or TICI score 2b-3). Univariate tests were followed by development of a multivariable model based on stepwise selection with entry and retention criteria of p < 0.05 from the set of factors with at least marginal significance (p ≤ 0.10) on univariate analysis. The c-statistic was calculated as a measure of predictive power. Results: Out of 354 patients, 256 (72.3%) were successfully recanalized (TICI ≥ 2b). Based on 90-day mRS score for 234 of these patients, there were 116 (49.6%) with mRS > 2. Univariate analysis identified increased risk of mRS > 2 for each of the following: age ≥ 80 years (upper quartile of data), occlusion site other than M1/M2, NIH Stroke Scale (NIHSS) score ≥ 18 (median), history of diabetes mellitus (DM), TICI = 2b, use of rescue therapy, not using a balloon-guided catheter (BGC) or intravenous tissue plasminogen activator (IV t-PA), and time to recanalization > 30 minutes (all p ≤ 0.05). Three or more passes was marginally significant (p=0.097). In multivariable analysis, age ≥ 80 years, site other than M1/M2, initial NIHSS ≥18, DM, absence of IV t-PA, use of rescue therapy and three or more passes were significant independent predictors of poor 90-day outcome in a model with good predictive power (c-index = 0.80). Conclusions: Age, occlusion site, high NIHSS, diabetes, not receiving IV t-PA, use of rescue therapy and three or more passes, were associated with poor 90-day outcome despite successful recanalization.


Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Muhammad U Farooq ◽  
Kathie Thomas

Objectives: Stroke is the fifth-leading cause of death and the leading cause of disability in the United States. One of the primary goals of the American Heart Association/American Stroke Association is to increase the number of acute stroke patients arriving at emergency departments (EDs) within 1-hour of symptom onset. Earlier treatment with thrombolysis in patients with acute ischemic stroke translates into improved patient outcomes. The objective of this abstract is to examine the association between the use of emergency medical services (EMS) and symptom onset-to-arrival time in patients with ischemic stroke. Methods: A retrospective review of ischemic stroke patients (n = 8873) from 25 Michigan hospitals from January 2012-December 2014 using Get With the Guidelines databases was conducted. Symptom onset-to-ED arrival time and arrival mode were examined. Results: It was found that 17.4% of ischemic stroke patients arrived at the hospitals within 1-hour of symptom onset. EMS transported 69.1% of patients who arrived within 1-hour of symptom onset. During this 1-hour period African American patients (22%) were less likely to use EMS transportation as compared to White patients (72%). The majority of patients, 41.8%, arrived after 6-hours of symptom onset. EMS transported only 40% of patients who arrived after 6-hours of symptom onset. As before, during this 6-hour period African American patients (20%) were also less likely to use EMS transportation as compared to White patients (75%). Symptom onset-to-ED arrival time was shorter for those patients who used EMS. The median pre-hospital delay time was 2.6 hours for those who used EMS versus 6.2 hours for those who did not use EMS. Conclusions: The use of EMS is associated with a decreased pre-hospital delay, early treatment with thrombolysis and improved patient outcomes in ischemic stroke patients. Community interventions should focus on creating awareness especially in minority populations about stroke as a neurological emergency and encourage EMS use amongst stroke patients.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Nicolle W Davis ◽  
Meghan Bailey ◽  
Natalie Buchwald ◽  
Amreen Farooqui ◽  
Anna Khanna

Background/Objective: There is growing importance on discovering factors that delay time to intervention for acute ischemic stroke (AIS) patients, as rapid intervention remains essential for better patient outcomes. The management of these patients involves a multidisciplinary effort and quality improvement initiatives to safely increase treatment with intravenous thrombolytic (IV tPa). The objective of this pilot is to evaluate factors of acute stroke care in the emergency department (ED) and the impact they have on IV tPa administration. Methods: A sample of 89 acute ischemic stroke patients that received IV tPa from a single academic medical institution was selected for retrospective analysis. System characteristics (presence of a stroke nurse and time of day) and patient characteristics (mode of arrival and National Institutes of Health Stroke Scale score (NIHSS) on arrival) were analyzed using descriptive statistics and multiple regression to address the study question. Results: The mean door to needle time is 53.74 minutes ( + 38.06) with 74.2% of patients arriving to the ED via emergency medical services (EMS) and 25.8% having a stroke nurse present during IV tPa administration. Mode of arrival ( p = .001) and having a stroke nurse present ( p = .022) are significant predictors of door to needle time in the emergency department (ED). Conclusion: While many factors can influence door to needle times in the ED, we did not find NIHSS on arrival or time of day to be significant factors. Patients arriving to the ED by personal vehicle will have a significant delay in IV tPa administration, therefore emphasizing the importance of using EMS. Perhaps more importantly, collaborative efforts including the addition of a specialized stroke nurse significantly decreased time to IV tPa administration for AIS patients. With this dedicated role, accelerated triage and more effective management of AIS patients is accomplished, leading to decreased intervention times and potentially improving patient outcomes.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Tri Huynh* ◽  
Niran Vijayaraghavan* ◽  
Hannah Branstetter ◽  
Natalie Buchwald ◽  
Justin De Prey ◽  
...  

Introduction: Hyperintense acute reperfusion marker (HARM) has been identified on post-contrast magnetic resonance imaging (MRI) to be a marker of hemorrhagic conversion (HC) post reperfusion therapy in acute stroke patients. We have previously described a case where MRI HARM was mimicked on post contrast computed topography (CT) imaging in an acute stroke patient post reperfusion. Dual-Energy (DECT) allows for differentiation between acute blood and iodine contrast extravasation (ICE), and thus can have utility when ICE is present. Here we sought to validate whether post-intervention ICE/CT hyperdensity reperfusion maker (CT HARM), and contrast subtracted on DECT is associated with HC in acute stroke patients. Method: Data was obtained from our Institutional Review Board approved stroke admission database from January 2017 to November 2019, including ischemic stroke patients that received thrombolysis or thrombectomy, had evaluable images within 24 hours of admission, and received a DECT. Ischemic volumes of the stroke was measured on diffusion-weighted image (DWI). ICE was measured on CT head and DECT using the freehand 3D region of interest tool on the Visage Imaging PACS System. Susceptibility weighted MRI sequences were used to grade HC. Data analysis was conducted with regression modeling. Results: A total of 82 patients were included, 49% women, median age 73 (interquartile range (IQR), 61- 77), admission NIHSS 12 (IQR, 7 - 21), 24 hour change in NIHSS 4 (IQR, 0 -13), glucose 125 (IQR, 106 -158), creatinine 1.0 (IQR, 0.8 - 1.2), infarct volume 50.6 ± 7.1 mL, 48% treated with thrombectomy, 7% with PH-1 or PH-2 identified on MRI, and 56% with MCA infarcts. ICE volume was 2.6 ± 1.0 mL and DECT volume was 2.2 ± 1.1mL. ICE increased the likelihood of MRI confirmed PH-1 or PH-2 hemorrhagic conversion (odds ratio (OR) 14.34, 95% confidence interval (CI) 5.74 - 22.94) and decreased likelihood of increase in NIHSS at 24 hours (OR 0.20, 95% CI 0.01 to 0.40). There were no other significant associations with ICE or DECT volumes. Conclusion: Our results are supportive of our proposed association between CT HARM and risk of HC. More studies are needed to study whether quantitative of DECT can be predictive of stroke outcomes post reperfusion therapy.


Sign in / Sign up

Export Citation Format

Share Document