Abstract WP492: Differential Effects of Iron Chelation With Deferoxamine on Post-Stroke Neurovascular Inflammation: Disease and Sex Interactions

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Victoria L Wolf ◽  
Weiguo Li ◽  
Yasir Abdul ◽  
Guangkuo Dong ◽  
Rebecca Ward ◽  
...  
Keyword(s):  
Functional Outcomes ◽  
Microglial Activation ◽  
Iron Chelation ◽  
Artery Occlusion ◽  
Significant Loss ◽  
Cognitive Outcomes ◽  
Mesenchymal Transition ◽  
Differential Effects ◽  
Post Stroke ◽  
Neurovascular Remodeling

We have shown that 1) poor recovery in diabetes is associated with greater hemorrhagic transformation and significant loss of the cerebrovasculature, and 2) iron chelation therapy with deferoxamine (DFX) improves sensorimotor and cognitive outcomes while preventing vasoregression in male diabetic animals after stroke. This study tested the hypotheses that 1) diabetes mediates pathological post-stroke neovascularization in females and 2) DFX attenuates microglial activation and pathological neurovascular remodeling in both sexes. Control and diabetic animals were subjected to embolic middle cerebral artery occlusion (MCAO). DFX (100 mg/kg) or vehicle was given 1hour after MCAO and repeated every 12h for 7 days after stroke. Functional outcomes were assessed over time. Vascular indices, microglial morphology (activation), and neurovascular integrity (IgG and unpolarized Aquaporin-4) were measured at Day 14. Male and female microvascular endothelial cells (BMVECs) treated with iron and/or DFX were tested for viability and endothelial mesenchymal transition (EndMT) markers. DFX preserved vascular volume post-stroke in diabetic males. Stroke did not cause vasoregression in diabetic female animals; however, DFX reduced vascular indices while improving sensorimotor but not cognitive outcomes in both control and diabetic females. Ischemic injury amplified microglial activation and neurovascular remodeling in diabetes while DFX treatment restored these changes to control levels in male diabetic animals but not in females (Table). Female BMVECs grown under diabetic conditions expressed α-SMA and N-cadherin while VE-cadherin was decreased, indicative of EndMT (p<0.05 vs normal glucose). Data suggest that DFX treatment has sex- and disease-dependent effects on post-stroke neovascularization. Additional studies will aim to address the mechanisms by which DFX exerts these differential effects on functional outcomes and neurovascular remodeling.

scholarly journals Poststroke cognitive impairment and hippocampal neurovascular remodeling: the impact of diabetes and sex

2018 ◽  
Vol 315 (5) ◽  
pp. H1402-H1413 ◽  
Author(s):  
Rebecca Ward ◽  
John Paul Valenzuela ◽  
Weiguo Li ◽  
Guangkuo Dong ◽  
Susan C. Fagan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Microglial Activation ◽  
Neuronal Degeneration ◽  
Artery Occlusion ◽  
Cognitive Outcomes ◽  
Stroke Severity ◽  
Male And Female ◽  
Neuronal Density ◽  
Neurovascular Remodeling ◽  
The Impact

Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. Pathological remodeling of the cerebrovasculature has been postulated to contribute to poor neuronal repair and worsened cognitive deficits in diabetes. However, little is known about the effect of diabetes on the vascularization of hippocampus, a domain critical to memory and learning. Therefore, we had two aims for this study: 1) to determine the impact of diabetes on hippocampal neurovascular remodeling and the resulting cognitive impairment after stroke using two models with varying disease severity, and 2) to compare the effects of ischemia on hippocampal neurovascular injury in diabetic male and female animals. Stroke was induced by middle cerebral artery occlusion (MCAO) by either the suture or embolic method in control and diabetic age-matched male and female Wistar rats. Hippocampal neuronal density, vascular architecture, and microglial activation as well as cognitive outcomes were measured. Embolic MCAO induced greater neuronal degeneration, pathological vascularization, microglial activation, and cognitive impairment in diabetes as compared with control animals or 60-min MCAO. Although diabetic males had lower neuronal density at baseline, diabetic females had more neurodegeneration after stroke. Control animals recovered cognitive function by day 14 after stroke; diabetic animals showed deficits regardless of sex. These results suggest that mechanisms underlying cognitive decline in diabetes may differ in males and females and provide further insight to the impact of diabetes on stroke severity and poststroke cognitive impairment. NEW & NOTEWORTHY The present study is the first to provide comparative information on the effects of diabetes and ischemia on cognitive outcomes in both sexes while also evaluating the neurovascular structure in the hippocampus, a critical region for cognitive and memory-related tasks.

Abstract P735: QPCR Panel Profiling Reveals MiRNAs That Modulate Microglial Activation in Aged Males Isolated After Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Anik Banerjee ◽  
Anil Kiran Chokkalla ◽  
Julia Shi ◽  
Juneyoung Lee ◽  
Venugopal Reddy Venna ◽  
...  
Keyword(s):  
Social Isolation ◽  
Microglial Activation ◽  
Artery Occlusion ◽  
Post Stroke ◽  
Intracellular Release ◽  
Immune Mediated ◽  
Microglial Phenotype ◽  
Novel Biomarkers ◽  
Underlying Mechanisms ◽  
Cerebral Artery Occlusion

Introduction: Social isolation (SI) after stroke is associated with increased ischemic injury and significantly delayed recovery due to exacerbation of microglial activation and immune mediated pro-inflammatory mechanisms. Studies have identified miRNAs that modulate and regulate this inflammatory transition through inflammasome NLRP3 activation. However, studies examining miRNA-based microglial activation in SI within the neuro-immune landscape are limited. We investigated miRNA profiles in aged mice to provide biomarkers and to identify underlying mechanisms related to microglial activation within the cerebral environment to mitigate this pathological microglial phenotype. Methods: Aged C57BL/6 male mice (18-20 months) were subjected to a 60-minute middle cerebral artery occlusion (MCAO) followed by reperfusion and were assigned to either (SI) or continued pair-housing (PH) immediately after stroke. On day 15, mice were sacrificed, and plasma samples were subjected to microRNAome (miRNAome) analysis. Top miRNAs were identified using bioinformatics frameworks and pathway analysis was performed using KEGG platform. Flow Cytometry (FACS) was performed on brain tissue and blood to determine if stroke or SI leads to changes in microglial and systemic myeloid activation. Results: The whole miRNAome panel analysis revealed 12 differentially expressed miRNAs (FC of 3 or higher) within the plasma following volcano plot and unsupervised hierarchical clustering analysis confirmed by qPCR validation (P< 0.05). Network analysis revealed miR-495-3p as a pivotal node that targeted the largest subset of immune specific genes (P< 0.05); most notable for the inflammasome NLRP3, a regulator of microglial activation. Significant microglial activation was seen in post-stroke SI mice compared to pair-housed cohorts, identified through MHC-II presentation and the intracellular release of pro-inflammatory cytokines. Conclusion: This study provides an overview of the miRNA changes induced by post-stroke isolation. Additionally, these results suggest that there is potential to use plasma-based miRNAs as a source of novel biomarkers. Further, microglial inflammasome specific pathways appear to be involved in post-stroke social isolation.

LncRNAs a New Target for Post-Stroke Recovery

2020 ◽  
Vol 26 (26) ◽  
pp. 3115-3121
Author(s):  
Jun Yang ◽  
Jingjing Zhao ◽  
Xu Liu ◽  
Ruixia Zhu
Keyword(s):  
Ischemic Stroke ◽  
Microglial Activation ◽  
Vital Role ◽  
Stroke Recovery ◽  
Biological Processes ◽  
Current Development ◽  
Post Stroke ◽  
Cascade Processes ◽  
Non Coding Rnas ◽  
Neuron Injury

LncRNAs (long non-coding RNAs) are endogenous molecules, involved in complicated biological processes. Increasing evidence has shown that lncRNAs play a vital role in the post-stroke pathophysiology. Furthermore, several lncRNAs were reported to mediate ischemia cascade processes include apoptosis, bloodbrain barier breakdown, angiogenesis, microglial activation induced neuroinflammation which can cause neuron injury and influence neuron recovery after ischemic stroke. In our study, we first summarize current development about lncRNAs and post-stroke, focus on the regulatory roles of lncRNAs on pathophysiology after stroke. We also reviewed genetic variation in lncRNA associated with functional outcome after ischemic stroke. Additionally, lncRNA-based therapeutics offer promising strategies to decrease brain damage and promote neurological recovery following ischemic stroke. We believe that lncRNAs will become promising for the frontier strategies for IS and can open up a new path for the treatment of IS in the future.

scholarly journals Post-Stroke Depression and Its Effect on Functional Outcomes during Inpatient Rehabilitation

2021 ◽  
Author(s):  
Gurumayum Sonachand Sharma ◽  
Anupam Gupta ◽  
Meeka Khanna ◽  
Naveen Bangarpet Prakash
Keyword(s):  
Outcome Measures ◽  
Functional Outcomes ◽  
Rating Scale ◽  
Tertiary Care ◽  
Depression Scale ◽  
Inpatient Rehabilitation ◽  
University Hospital ◽  
Post Stroke ◽  
Significant Difference ◽  
Post Stroke Depression

Abstract Objective The aim of the study is to observe the effect of post-stroke depression on functional outcomes during inpatient rehabilitation. Patients and Methods The design involved is prospective observational study. The location involved is Neurological Rehabilitation unit in a tertiary care university hospital. The study period ranges from October 2019 to April 2020. The participants involved are the patients with first ever stroke, male and female with age ≥18 years and duration less than 1 year. All participants were assessed at admission and after 14 sessions of inpatient rehabilitation by depression subscale of Hospital Anxiety and Depression Scale (HADS-D) and Hamilton Depression Rating Scale (HDRS). The stroke outcomes measures used were: Barthel Index (BI), Scandinavian Stroke Scale (SSS), and Modified Rankin Scale (MRS). Results There are a total of 30 participants (18 males) with median stroke duration of 90 days. The median age of the patients was 58 years. Sixteen patients had ischemic and 14 had hemorrhagic stroke. Out of these, 57% (n = 17) had symptoms of depression (HADS-D >7). Participants in both groups (with and without depression) showed improvement in all the functional outcome measures (BI, SSS, MRS) at the time of discharge as compared with admission scores. The changes in the outcome measures were statistically significant within groups (p < 0.05) but not significant between the groups (p > 0.05). Conclusion The post-stroke depression is common among stroke survivors of less than 1 year duration. There was no significant difference in the functional outcomes between stroke patients with depression and those without depression with inpatient rehabilitation program.

Abstract W P222: Activated Microglia Contribute to Neurovascular Integrity and Limit Brain Injury After Acute Neonatal Focal Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
David Fernández-López ◽  
Joel Faustino ◽  
Alexander Klibanov ◽  
Nikita Derugin ◽  
katerina Akassoglou ◽  
...  
Keyword(s):  
Brain Injury ◽  
Microglial Activation ◽  
Injury Severity ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Microglial Cells ◽  
Vascular Density ◽  
Relative Role ◽  
Morphological Transformation ◽  
Activated Microglia

It has been recently shown that microglial cells, which for a long time were considered purely injurious in the context of cerebral ischemia, can also exert beneficial effects following stroke in both adults and neonates1,2. Lack of tools to reliably distinguish resident microglia from infiltrated peripheral monocytes has been a major obstacle on the way to understand the relative role of these subpopulations of cells of the monocyte lineage in the pathophysiology of stroke. We subjected postnatal day 10 (P10) transgenic Cx3cr1GFP/-CCr2RFP/- mice, in which resident microglia (Cx3cr1GFP) and infiltrating monocytes (CCr2RFP) can be distinctively identified, to a transient 3 hour middle cerebral artery occlusion MCAO, a model that we recently developed3. Microglial cells were left unperturbed or were selectively depleted before MCAO by intracortical injection of clodronate-encapsulated liposomes. Depletion of microglia exacerbated injury and significantly increased infarct volume (75.9% Vs. 56.3%, p<0.01). Furthermore, compared to mice with unperturbed microglia, depletion of microglia significantly increased the number of hemorrhages in injured regions, adversely affected vascular density and decreased the number of both adherent and infiltrated monocytes. The extent of RFP+ monocyte adhesion to vessels and infiltration in the brain parenchyma was highly variable among individual mice and did not correlate with brain infarct, whereas a significant correlation between the overall extent of microglial activation (measured by morphological transformation) and the number of infiltrated monocytes was observed. The deleterious effect of microglial depletion on vascular integrity and function and on brain injury indicates that activated microglia act as a buffering component that limits vascular degeneration and injury severity after neonatal stroke. Our data also suggest a direct and dynamic relationship between microglial activation and monocyte recruitment into acutely reperfused neonatal brain. Support: NS55915 (ZV), NS76726 (ZV), NS080015 (ZS, KA), AHA POST10980003 (DFL). 1. Faustino J et al. J Neurosci. 2011. 2. Lalancette-Hebert M et al. J Neurosci. 2007. 3. Woo MS et al. Annals of Neurology. 2012.

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 Effects of Veliparib on Microglial Activation and Functional Outcomes after Traumatic Brain Injury in the Rat and Pig

2018 ◽  
Vol 35 (7) ◽  
pp. 918-929 ◽  
Author(s):  
Karen-Amanda Irvine ◽  
Robin K. Bishop ◽  
Seok Joon Won ◽  
Jianguo Xu ◽  
Katherine A. Hamel ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Functional Outcomes ◽  
Microglial Activation

scholarly journals Inhibition of Vascular Nitric Oxide after Rat Chronic Brain Hypoperfusion: Spatial Memory and Immunocytochemical Changes

2005 ◽  
Vol 25 (6) ◽  
pp. 663-672 ◽  
Author(s):  
Jack C. de la Torre ◽  
Gjumrakch Aliev
Keyword(s):  
Nitric Oxide ◽  
Spatial Memory ◽  
Memory Function ◽  
Critical Role ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Significant Loss ◽  
Electron Microscopic ◽  
Vessel Occlusion ◽  
Common Carotid Artery Occlusion

An aging rat model of chronic brain hypoperfusion (CBH) that mimics human mild cognitive impairment (MCI) was used to examine the role of nitric oxide synthase (NOS) isoforms on spatial memory function. Rats with CBH underwent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) for either 26 or 8 weeks and were compared with nonoccluded sham controls (S-VO). The neuronal and endothelial (nNOS/eNOS) constitutive inhibitor nitro-L-arginine methyl ester (L-NAME) 20 mg/kg was administered after 26 weeks for 3 days to 2-VO and S-VO groups and spatial memory was assessed with a modified Morris watermaze test. Only 2-VO rats worsened their spatial memory ability after L-NAME. Electron microscopic immunocytochemical examination using an antibody against eNOS showed 2-VO rats had significant loss or absence of eNOS-containing positive gold particles in hippocampal endothelium and these changes were associated with endothelial cell compression, mitochondrial damage and heavy amyloid deposition in hippocampal capillaries and perivascular region. In the 8-week study, three groups of 2-VO rats were administered an acute dose of 7-NI, aminoguanidine or L-NIO, the relatively selective inhibitors of nNOS, inducible NOS and eNOS. Only rats administered the eNOS inhibitor L-NIO worsened markedly their watermaze performance ( P=0.009) when compared with S-VO nonoccluded controls. We conclude from these findings that vascular nitric oxide derived from eNOS may play a critical role in spatial memory function during CBH possibly by keeping cerebral perfusion optimal through its regulation of microvessel tone and cerebral blood flow and that disruption of this mechanism can result in spatial memory impairment. These findings may identify therapeutic targets for preventing MCI and treating Alzheimer's disease.

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