Genetic deletion of endothelial microRNA-15a/16-1 promotes cerebral angiogenesis and neurological recovery in ischemic stroke through Src signaling pathway

2021 ◽  
pp. 0271678X2110103
Author(s):  
Ping Sun ◽  
Feifei Ma ◽  
Yang Xu ◽  
Chao Zhou ◽  
R. Anne Stetler ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Artery Occlusion ◽  
Conditional Knockout ◽  
Neurological Recovery ◽  
Wild Type Littermate ◽  
Signaling Mechanism ◽  
Post Stroke ◽  
Src Signaling

Cerebral angiogenesis is tightly controlled by specific microRNAs (miRs), including the miR-15a/16-1 cluster. Recently, we reported that endothelium-specific conditional knockout of the miR-15a/16-1 cluster (EC-miR-15a/16-1 cKO) promotes post-stroke angiogenesis and improves long-term neurological recovery by increasing protein levels of VEGFA, FGF2, and their respective receptors VEGFR2 and FGFR1. Herein, we further investigated the underlying signaling mechanism of these pro-angiogenic factors after ischemic stroke using a selective Src family inhibitor AZD0530. EC-miR-15a/16-1 cKO and age- and sex-matched wild-type littermate (WT) mice were subjected to 1 h middle cerebral artery occlusion (MCAO) and 28d reperfusion. AZD0530 was administered daily by oral gavage to both genotypes of mice 3-21d after MCAO. Compared to WT, AZD0530 administration exacerbated spatial cognitive impairments and brain atrophy in EC-miR-15a/16-1 cKO mice following MCAO. AZD0530 also attenuated long-term recovery of blood flow and inhibited the formation of new microvessels, including functional vessels with blood circulation, in the penumbra of stroked cKO mice. Moreover, AZD0530 blocked the Src signaling pathway by downregulating phospho-Src and its downstream mediators (p-Stat3, p-Akt, p-FAK, p-p44/42 MAPK, p-p38 MAPK) in post-ischemic brains. Collectively, our data demonstrated that endothelium-targeted deletion of the miR-15a/16-1 cluster promotes post-stroke angiogenesis and improves long-term neurological recovery via activating Src signaling pathway.

Abstract 112: Genetic Deletion of Endothelial microRNA-15a/16-1 Promotes Cerebral Angiogenesis and Neurological Recovery in Ischemic Stroke Through Src Signaling Pathway

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ping Sun ◽  
Feifei Ma ◽  
Chao Zhou ◽  
R. Anne Stetler ◽  
Jun Chen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Brain Atrophy ◽  
Conditional Knockout ◽  
Neurological Recovery ◽  
Targeted Deletion ◽  
Post Stroke ◽  
Src Signaling ◽  
Genetic Deletion

Introduction: Cerebral angiogenesis is tightly controlled by certain microRNAs (miRs), such as the miR-15a/16-1 cluster, among others. Recently, we demonstrated that endothelium-targeted deletion of miR-15a/16-1 promotes post-stroke angiogenesis and improves long-term neurological recovery by increasing protein levels of VEGFA, FGF2, and their receptors VEGFR2 and FGFR1. Here, we further investigated the downstream signaling pathways of these pro-angiogenic factors by using a potent Src family inhibitor, saracatinib (AZD0530), in endothelial cell-selective miR-15a/16-1 conditional knockout (EC-miR-15a/16-1 cKO) mice after ischemic stroke. Hypothesis: Pharmacological inhibition of Src signaling cascade using AZD0530 diminishes enhanced post-stroke angiogenesis and long-term neurological recovery induced by the genetic deletion of miR-15a/16-1 in the endothelium. Methods: EC-miR-15a/16-1 cKO and WT littermate controls were subjected to 1h MCAO and 28d reperfusion. AZD0530 (20 mg/kg) was administered daily to both genotypes at 3-21d after MCAO by oral gavage. Cognitive outcomes were determined by Morris water maze tests. Brain atrophy was measured by MAP2 immunostaining. Cerebral blood flow (CBF) was monitored by laser speckle imaging. Brain capillary density and functional vessels were examined by CD31/BrdU and tomato lectin/BrdU double-immunostaining, respectively. Src signaling pathway-related molecules were analyzed by western blotting. Results: Treatment with AZD0530 exacerbates cognitive impairments and brain atrophy in EC-miR-15a/16-1 cKO mice following MCAO. AZD0530 also attenuates the long-term CBF recovery, correlated with inhibiting the generation of newly formed microvessels and functional vessels in the peri-infarct brain regions in EC-miR-15a/16-1 cKO mice after cerebral ischemia. Moreover, EC-targeted deletion of miR-15a/16-1 upregulates the Src signaling pathway, while AZD0530 blocks the Src signaling pathway by downregulating p-Src and its downstream mediators (p-Stat3, p-Akt, p-FAK, p-p38 MAPK) in ischemic brains. Conclusions: Endothelium-targeted deletion of miR-15a/16-1 promotes post-stroke angiogenesis and improves long-term neurological recovery via Src signaling pathway.

scholarly journals Effects of long-term anti-seizure medication monotherapy on all-cause death in patients with post-stroke epilepsy: a nationwide population-based study in Taiwan

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chia-Yu Hsu ◽  
Chun-Yu Cheng ◽  
Jiann-Der Lee ◽  
Meng Lee ◽  
Bruce Ovbiagele
Keyword(s):  
Valproic Acid ◽  
Ischemic Stroke ◽  
Cox Regression ◽  
Population Based ◽  
Primary Diagnosis ◽  
Research Database ◽  
Post Stroke ◽  
Risk Of Death ◽  
Index Stroke

Abstract Objective We aim to compare the effect of long-term anti-seizure medication (ASM) monotherapy on the risk of death and new ischemic stroke in patients with post-stroke epilepsy (PSE). Patients and methods We identified all hospitalized patients (≥ 20 years) with a primary diagnosis of ischemic or hemorrhagic stroke from 2001 to 2012 using the National Health Insurance Research Database in Taiwan. The PSE cohort were defined as the stroke patients (1) who had no epilepsy and no ASMs use before the index stroke, and (2) who had epilepsy and ASMs use after 14 days from the stroke onset. The patients with PSE receiving ASM monotherapy were enrolled and were categorized into phenytoin, valproic acid, carbamazepine, and new ASM groups. We employed the Cox regression model to estimate the unadjusted and adjusted hazard ratios (HRs) with 95 % confidence intervals (CIs) of death and new ischemic stroke within 5 years across all groups, using the new ASM group as the reference. Results Of 6962 patients with PSE using ASM monotherapy, 3917 (56 %) were on phenytoin, 1623 (23 %) on valproic acid, 457 (7 %) on carbamazepine, and 965 (14 %) on new ASMs. After adjusting for confounders, compared with new ASM users, phenytoin users had a higher risk of death in 5 years (HR: 1.64; 95 % CI: 1.06–2.55). On the other hand, all ASM groups showed a similar risk of new ischemic stroke in 5 years. Conclusions Among patients with PSE on first-line monotherapy, compared to new ASMs, use of phenytoin was associated with a higher risk of death in 5 years.

Abstract WP7: Leukoaraiosis And Outcomes After Intra-arterial Therapy In Acute Ischemic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Dan-Victor V Giurgiutiu ◽  
Albert J Yoo ◽  
Kaitlin Fitzpatrick ◽  
Zeshan Chaudhry ◽  
Lee H Schwamm ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Artery Occlusion ◽  
Post Stroke ◽  
Good Functional Outcome ◽  
Grade 3 ◽  
Risk Of Hemorrhage

Background: Selecting patients most likely to benefit (MLTB) from intra-arterial therapy (IAT) is essential to assure favorable outcomes after intervention for acute ischemic stroke (AIS). Leukoaraiosis (LA) has been linked to infarct growth, risk of hemorrhage after IV rt-PA, and poor post-stroke outcomes. We investigated whether LA severity is associated with AIS outcomes after IAT. Methods: We analyzed consecutive AIS subjects from our institutional GWTG-Stroke database enrolled between 01/01/2007-06/30/2009, who met our pre-specified criteria for MLTB: CTA and MRI within 6 hours from last known well, NIHSS score ≥8, baseline DWI volume (DWIv) ≤ 100 cc, and proximal artery occlusion and were treated with IAT. LA volume (LAv) was assessed on FLAIR using validated, semi-automated protocols. We analyzed CTA to assess collateral grade; post-IAT angiogram for recanalization status (TICI score ≥2B); and the 24-hour CT for symptomatic ICH (sICH). Logistic regression was used to determine independent predictors of good functional outcome (mRS≤ 2) and mortality at 90 days post-stroke. Results: There were 48 AIS subjects in this analysis (mean age 69.2, SD±13.8; 55% male; median LAv 4cc, IQR 2.2-8.8cc; median NIHSS 15, IQR 13-19; median DWIv 15.4cc, IQR 9.2-20.3cc). Of these, 34 (72%) received IV rt-PA; 3 (6%) had sICH; 21 (44.7%) recanalized; and 23 (50%) had collateral grade ≥3. At 90 days, 15/48 (36.6%) were deceased and 15/48 had mRS≤ 2. In univariate analysis, recanalization (OR 6.2, 95%CI 1.5-25.5), NIHSS (OR 0.8 per point, 95%CI 0.64-0.95), age (OR 0.95 per yr, 95%CI 0.89-0.99) were associated with good outcome, whereas age (OR 1.1, 95%CI 1.01-1.14) and HTN (OR 5.6, 95%CI 1.04-29.8) were associated with mortality. In multivariable analysis including age, NIHSS, recanalization, collateral grade, and LAv, only recanalization independently predicted good functional outcome (OR 21.3, 95%CI 2.3-199.9) and reduced mortality (OR 0.15, 95%CI 0.02-1.12) after IAT. Conclusions: LA severity is not associated with poor outcome in patients selected MLTB for IAT. Among AIS patients considered likely to benefit from IAT, only recanalization independently predicted good functional outcome and decreased mortality.

scholarly journals Twenty-Year Time Trends in Long-Term Case-Fatality and Recurrence Rates After Ischemic Stroke Stratified by Etiology

Stroke ◽  
2020 ◽  
Vol 51 (9) ◽  
pp. 2778-2785 ◽  
Author(s):  
Viktoria Rücker ◽  
Peter U. Heuschmann ◽  
Martin O’Flaherty ◽  
Michael Weingärtner ◽  
Manuela Hess ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Time Trends ◽  
Cox Regression ◽  
Case Fatality ◽  
Population Based ◽  
Artery Occlusion ◽  
Recurrence Rates ◽  
Term Survival ◽  
Small Artery Occlusion

Background and Purpose: Data on long-term survival and recurrence after stroke are lacking. We investigated time trends in ischemic stroke case-fatality and recurrence rates over 20-years stratified by etiological subtype according to the Trial of ORG 10172 in Acute Stroke Treatment classification within a population-based stroke register in Germany. Methods: Data was collected within the Erlangen Stroke Project, a prospective, population-based stroke register covering a source population of 105 164 inhabitants (2010). Case fatality and recurrence rates for 3 months, 1 year, and 5 years were estimated with Kaplan-Meier estimates. Sex-specific time trends for case-fatality and recurrence rates were estimated with Cox regression. We adjusted for age, sex, and year of event and stratified for etiological subtypes. A sensitivity analysis with competing risk analysis for time trends in recurrence were performed. Results: Between 1996 and 2015, 3346 patients with first ischemic stroke were included; age-standardized incidence per 100 000 was 75.8 in women and 131.6 in men (2015). Overall, 5-year survival probabilities were 50.4% (95% CI, 47.9–53.1) in women and 59.2% (95% CI, 56.4–62.0) in men; 5-year survival was highest in patients with first stroke due to small-artery occlusion (women, 71.8% [95% CI, 67.1–76.9]; men, 75.9% [95% CI, 71.3–80.9]) and lowest in cardioembolic stroke (women, 35.7% [95% CI, 31.0–41.1]; men, 47.8% [95% CI, 42.2–54.3]). Five-year recurrence rates were 20.1% (95% CI, 17.5–22.6) in women and 20.1% (95% CI, 17.5–22.7) in men; 5-year recurrence rate was lowest in women in stroke due to small artery occlusion 16.0% (95% CI, 11.7–20.1) and in men in large-artery atherosclerosis 16.6% (95% CI, 8.7–23.9); highest risk of recurrence was observed in undefined strokes (women, 22.3% [95% CI, 17.8–26.6]; men, 21.4% [95% CI, 16.7–25.9]). Cox regression revealed improvements in case-fatality rates over time with differences in stroke causes. No time trends in recurrence rates were observed. Conclusions: Long-term survival and recurrence varied substantially by first stroke cause. Survival probabilities improved over the past 2 decades; no major trends in stroke recurrence rates were observed.

scholarly journals Infarct topography and functional outcomes

2017 ◽  
Vol 38 (9) ◽  
pp. 1517-1532 ◽  
Author(s):  
Mark R Etherton ◽  
Natalia S Rost ◽  
Ona Wu
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcomes ◽  
Brain Regions ◽  
Stroke Recovery ◽  
Acute Ischemia ◽  
Post Stroke ◽  
Neurologic Outcomes ◽  
Recovery Potential

Acute ischemic stroke represents a major cause of long-term adult disability. Accurate prognostication of post-stroke functional outcomes is invaluable in guiding patient care, targeting early rehabilitation efforts, selecting patients for clinical research, and conveying realistic expectations to families. The involvement of specific brain regions by acute ischemia can alter post-stroke recovery potential. Understanding the influences of infarct topography on neurologic outcomes holds significant promise in prognosis of functional recovery. In this review, we discuss the recent evidence of the contribution of infarct location to patient management decisions and functional outcomes after acute ischemic stroke.

scholarly journals The regulation of glycemia in the recovery phase after stroke counteracts the detrimental effect of obesity-induced type 2 diabetes on neurological recovery

2020 ◽  
Author(s):  
Ada Admin ◽  
Ingrid Lovise Augestad ◽  
Hiranya Pintana ◽  
Martin Larsson ◽  
Camilla Krizhanovskii ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Clinical Situation ◽  
Recovery Phase ◽  
Artery Occlusion ◽  
Stroke Recovery ◽  
Neurological Recovery ◽  
Standard Diet ◽  
Dipeptidyl Peptidase 4 ◽  
Post Stroke ◽  
The Impact

The interplay between obesity and T2D in post-stroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. <p>We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically-used T2D drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride.</p> <p>We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet (HFD)) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the post-stroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks.<b> </b>We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis and atrophy of parvalbumin (PV)+ interneurons were quantified by immunohistochemistry.</p> <p>T2D/obesity impaired post-stroke neurological recovery in association with hyperglycemia, neuroinflammation and atrophy of PV+ interneurons. Both drugs counteracted these effects. In non-diabetic mice, only linagliptin accelerated recovery.</p> These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies based on efficacious glycemia regulation, even if initiated days after stroke.

scholarly journals Post-stroke Hyperglycemia in Non-diabetic Ischemic Stroke is Related With Worse Functional Outcome: A Cohort Study

2021 ◽  
Vol 45 (5) ◽  
pp. 359-367
Author(s):  
Jin A Yoon ◽  
Yong-Il Shin ◽  
Deog Young Kim ◽  
Min Kyun Sohn ◽  
Jongmin Lee ◽  
...  
Keyword(s):  
Cohort Study ◽  
Ischemic Stroke ◽  
Glucose Level ◽  
Functional Outcomes ◽  
Stroke Patients ◽  
Nihss Score ◽  
Post Stroke ◽  
Significant Difference ◽  
Functional Assessments

Objective To investigate long-term and serial functional outcomes in ischemic stroke patients without diabetes with post-stroke hyperglycemia.Methods The Korean Stroke Cohort for Functioning and Rehabilitation (KOSCO) is a large, multi-center, prospective cohort study of stroke patients admitted to participating hospitals in nine areas of Korea. From KOSCO, ischemic stroke patients without diabetes were recruited and divided into two groups: patients without diabetes without (n=779) and with post-stroke hyperglycemia (n=223). Post-stroke hyperglycemia was defined as a glucose level >8 mmol/L. Functional assessments were performed 7 days and 3, 6, and 12 months after stroke onset.Results There were no significant differences in baseline characteristics between the groups, except in the age of onset and smoking. Analysis of the linear correlation between the initial National Institutes of Health Stroke Scale (NIHSS) score and glucose level showed no significant difference. Among our functional assessments, NIHSS, Fugl-Meyer Assessment (affected side), Functional Ambulatory Category, modified Rankin Scale, and Korean Mini-Mental State Examination (K-MMSE) showed statistically significant improvements in each group. All functional improvements except K-MMSE were significantly higher in patients without post-stroke hyperglycemia at 7 days and 3, 6, and 12 months.Conclusion The glucose level of ischemic stroke patients without diabetes had no significant correlation with the initial NIHSS score. The long-term effects of stress hyperglycemia showed worse functional outcomes in ischemic stroke patients without diabetes with post-stroke hyperglycemia.

scholarly journals Protection against Neurological Symptoms by Consuming Corn Silk Water Extract in Artery-Occluded Gerbils with Reducing Oxidative Stress, Inflammation, and Post-Stroke Hyperglycemia through the Gut-Brain Axis

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 168
Author(s):  
Jin Ah Ryuk ◽  
Byoung Seob Ko ◽  
Na Rang Moon ◽  
Sunmin Park
Keyword(s):  
Ischemic Stroke ◽  
Neuronal Cell Death ◽  
Cell Mass ◽  
Water Extract ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Sham Control ◽  
Β Cell ◽  
Post Stroke ◽  
Corn Silk

Corn silk (Stigma maydis), rich in flavonoids, is traditionally used to treat edema, depression, and hyperglycemia and may alleviate ischemic stroke symptoms in Chinese medicine. This study examined whether corn silk water extract (CSW) could alleviate ischemic stroke symptoms and post-stroke hyperglycemia in Mongolian gerbils with transient cerebral ischemia and reperfusion (I/R). After being given 0.05% (I/R-LCSW) and 0.2% (I/R-HCSW), 0.02% aspirin (I/R-aspirin), and cellulose (I/R-control) in their 40 energy% fat diets for three weeks, the gerbils underwent an artery occlusion for eight minutes and reperfusion. They took the assigned diet for an additional three weeks. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. CSW intake reduced neuronal cell death in gerbils with I/R and dose-dependently improved the neurological symptoms, including drooped eyes, crouched posture, flexor reflex, and walking patterns. CSW intake also alleviated the short-term memory and spontaneous alteration and grip strength compared to the I/R-control group. The protection against ischemic stroke symptoms was associated with the reduced tumor necrosis factor-α, interleukin-1β, superoxide, and lipid peroxide levels, promoting superoxide dismutase activity in the hippocampus in the CSW groups, compared to the I/R-control. The blood flow measured by Doppler was improved with CSW compared to the I/R-control. Furthermore, CSW intake prevented the post-stroke hyperglycemia related to decreasing pancreatic β-cell mass as much as the Sham-control, and it was related to protection against β-cell apoptosis, restoring the β-cell mass similar to the Sham-control. CSW intake elevated the relative abundance of Lactobacillus, Bifidobacterium, Allobaculum, and Akkermansia compared to the I/R-control. Picrust2 analysis showed that CSW increased the propionate and butyrate metabolism and the starch and glucose metabolism but reduced lipopolysaccharide biosynthesis compared to the I/R-control. In conclusion, CSW intake protects against neuronal cell death and post-hyperglycemia by reducing oxidative stress and inflammation and increasing blood flow and the β-cell mass. The alleviation was associated with promoting the gut-brain axis by changing the gut microbiome community.

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