scholarly journals Increased 20-HETE Signaling Suppresses Capillary Neurovascular Coupling After Ischemic Stroke in Regions Beyond the Infarct

2021 ◽  
Vol 15 ◽  
Author(s):  
Zhenzhou Li ◽  
Heather L. McConnell ◽  
Teresa L. Stackhouse ◽  
Martin M. Pike ◽  
Wenri Zhang ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Stroke Patients ◽  
Natural Inhibitor ◽  
Cerebral Artery Occlusion ◽  
Infarct Border ◽  
Capillary Dilation

Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ∼75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-hydroxyeicosatetraenoic acid (20-HETE), either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of endoperoxide 4 (EP4) receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levels in vivo and increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying capillary neurovascular coupling impairment after stroke. Our results suggest that the brain’s energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.

scholarly journals Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct

2021 ◽  
Author(s):  
Zhenzhou Li ◽  
Heather L McConnell ◽  
Teresa L Stackhouse ◽  
Martin M Pike ◽  
Wenri Zhang ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Stroke Patients ◽  
Natural Inhibitor ◽  
Cerebral Artery Occlusion ◽  
Infarct Border ◽  
Capillary Dilation

Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ~75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-HETE, either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of EP4 receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levels in vivo and increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying neurovascular coupling impairment after stroke. Our results suggest that the brain's energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.

scholarly journals Cerebral Organoids Repair Ischemic Stroke Brain Injury

2019 ◽  
Vol 11 (5) ◽  
pp. 983-1000 ◽  
Author(s):  
Shu-Na Wang ◽  
Zhi Wang ◽  
Tian-Ying Xu ◽  
Ming-He Cheng ◽  
Wen-Lin Li ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Stroke Treatment ◽  
Cell Based Therapy ◽  
Neural Apoptosis ◽  
Underlying Mechanisms ◽  
Cerebral Artery Occlusion

AbstractStroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment.

scholarly journals Increased serum QUIN/KYNA is a reliable biomarker of post-stroke cognitive decline

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Adrien Cogo ◽  
Gabrielle Mangin ◽  
Benjamin Maïer ◽  
Jacques Callebert ◽  
Mikael Mazighi ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Artery ◽  
Quinolinic Acid ◽  
Neuronal Death ◽  
Artery Occlusion ◽  
Serum Biomarkers ◽  
Diabetic Mice ◽  
Stroke Patients ◽  
Cerebral Artery Occlusion

Abstract Background Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments. As patients survive longer, post-stroke cognitive impairment (PSCI) has become a major health public issue. Diabetes has been identified as an independent predictive factor for PSCI. Here, we characterized a clinically relevant mouse model of PSCI, induced by permanent cerebral artery occlusion in diabetic mice, and investigated whether a reliable biomarker of PSCI may emerge from the kynurenine pathway which has been linked to inflammatory processes. Methods Cortical infarct was induced by permanent middle cerebral artery occlusion in male diabetic mice (streptozotocin IP). Six weeks later, cognitive assessment was performed using the Barnes maze, hippocampi long-term potentiation using microelectrodes array recordings, and neuronal death, white matter rarefaction and microglia/macrophages density assessed in both hemispheres using imunohistochemistry. Brain and serum metabolites of the kynurenin pathway were measured using HPLC and mass fragmentography. At last, these same metabolites were measured in the patient’s serum, at the acute phase of stroke, to determine if they could predict PSCI 3 months later. Results We found long-term spatial memory was impaired in diabetic mice 6 weeks after stroke induction. Synaptic plasticity was completely suppressed in both hippocampi along with increased neuronal death, white matter rarefaction in both striatum, and increased microglial/macrophage density in the ipsilateral hemisphere. Brain and serum quinolinic acid concentrations and quinolinic acid over kynurenic acid ratios were significantly increased compared to control, diabetic and non-diabetic ischemic mice, where PSCI was absent. These putative serum biomarkers were strongly correlated with degradation of long-term memory, neuronal death, microglia/macrophage infiltration and white matter rarefaction. Moreover, we identified these same serum biomarkers as potential predictors of PSCI in a pilot study of stroke patients. Conclusions we have established and characterized a new model of PSCI, functionally and structurally, and we have shown that the QUIN/KYNA ratio could be used as a surrogate biomarker of PSCI, which may now be tested in large prospective studies of stroke patients.

Abstract WMP41: Neuronal Sirt1 is Required for Resveratrol Preconditioning Induced Ischemic Tolerance

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Kevin B Koronowski ◽  
Isa Saul ◽  
Zachary Balmuth-Loris ◽  
Miguel Perez-Pinzon
Keyword(s):  
Knockout Mouse ◽  
Infarct Volume ◽  
Hypoxia Inducible Factor ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Tamoxifen Treatment ◽  
Neurological Score ◽  
Transcription Factor Activation ◽  
Cerebral Artery Occlusion

Introduction: Our previous work demonstrates that resveratrol, a naturally occurring polyphenol, protects against cerebral ischemia when administered 2 or 14 days prior to injury. Resveratrol activates Sirt1, an NAD + -dependent deacylase that regulates cellular metabolism. It has been postulated that neuronal Sirt1 directly mediates this neuroprotection but it remains to be empirically tested. Objective: The objective of this study was to generate an inducible, neuronal-specific Sirt1 knockout mouse and determine whether neuronal Sirt1 is necessary for resveratrol-induced ischemic tolerance. Methods: Twenty to twenty-five gram neuronal-specific Sirt1 knockout mice (Sirt1neu-/-) and WTs were induced with tamoxifen. Mice were randomized for 1) western blot; 2) resveratrol preconditioning (RPC; 10 mg/kg resveratrol i.p.) or vehicle (1.5% DMSO; 0.9% saline) treatment 2 days prior to 60 minute middle cerebral artery occlusion (MCAo); 3) untargeted primary metabolomics by GC-TOF-MS; or 4) transcription factor activation profiling. Twenty-four hours following MCAo, neurological score was used to assess functional outcome and infarct volume was quantified by TTC staining. Results: Tamoxifen treatment removed WT Sirt1 protein from major brain regions but not from heart (Figure 1A, n=3). In WT, RPC reduced infarct volume by 43.7% and improved neurological score by nearly 3 points, however these effects were lost in Sirt1neu-/- (Figure 1B, n=5-9). Compared to WT, metabolic profiles from Sirt1neu-/- displayed significantly altered glycolysis metabolites (Figure 1C, n=8). Activation of hypoxia inducible factor (HIF) was reduced by 48% in Sirt1neu-/- (Figure 1D, n=3). Conclusions: We generated and utilized an inducible, neuronal-specific knockout mouse to demonstrate that neuronal Sirt1 specifically is required for RPC-induced ischemic tolerance. Additionally, Sirt1 regulates glycolysis in the brain, possibly through its interaction with HIF.

scholarly journals Leukocyte-Endothelium Interactions during Permanent Focal Cerebral Ischemia in Mice

2004 ◽  
Vol 24 (6) ◽  
pp. 668-676 ◽  
Author(s):  
Hiroharu Kataoka ◽  
Seong-Woong Kim ◽  
Nikolaus Plesnila
Keyword(s):  
Cerebral Ischemia ◽  
Brain Damage ◽  
Molecular Mechanisms ◽  
Focal Cerebral Ischemia ◽  
Fluorescent Microscopy ◽  
Capillary Density ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
Adherent Leukocytes

The contribution of leukocyte infiltration to brain damage after permanent focal cerebral ischemia and the underlying molecular mechanisms are still unclear. Therefore, the aim of this study was to establish a mouse model for the visualization of leukocytes in the cerebral microcirculation in vivo and to investigate leukocyte-endothelial interaction (LEI) after permanent middle cerebral artery occlusion (MCAO). Sham-operated 129/Sv mice showed physiologic LEI in pial venules as observed by intravital fluorescent microscopy. Permanent focal cerebral ischemia induced a significant increase of LEI predominantly in pial venules. The number of rolling and adherent leukocytes reached 36.5 ± 13.2/100 μm × min and 22.5 ± 7.9/100 μm × min, respectively at 120 minutes after MCAO ( P = 0.016 vs. control). Of note, rolling and adherent leukocytes were also observed in arterioles of ischemic animals (7.3 ± 3.0/100 μm × min rolling and 3.0 ± 3.6/100 μm × min adherent). Capillary density was not different between groups. These results demonstrate that leukocytes accumulate in the brain not only after transient but also after permanent focal cerebral ischemia and may therefore contribute to brain damage after stroke without reperfusion.

Changes in synaptic density in the subacute phase after ischemic stroke: A 11C-UCB-J PET/MR study

2021 ◽  
pp. 0271678X2110477
Author(s):  
Laura Michiels ◽  
Nathalie Mertens ◽  
Liselot Thijs ◽  
Ahmed Radwan ◽  
Stefan Sunaert ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Standardized Uptake Value ◽  
Brain Regions ◽  
Asymmetry Index ◽  
Cerebellar Hemisphere ◽  
Future Research ◽  
Stroke Patients ◽  
Synaptic Density ◽  
Positron Emission

Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on in vivo synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with 11C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo 11C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional 11C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of 11C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratiolesion/controls = 0.67 ± 0.28, p = 0.00023). Moreover, 11C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = −0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower 11C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = −0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.

Abstract 2925: DWI-ASPECTS As A Predictor Of Neurological Recovery In Acute Stroke Patients With The Middle Cerebral Artery Occlusion Treated With IV t-PA.

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Junya Aoki ◽  
Kazumi Kimura ◽  
Yasuyuki Iguchi ◽  
Kensaku Shibazaki ◽  
Noriko Matsumoto ◽  
...  
Keyword(s):  
Acute Stroke ◽  
Middle Cerebral Artery ◽  
Artery Occlusion ◽  
Neurological Recovery ◽  
Stroke Patients ◽  
Short Term ◽  
Nihss Score ◽  
Point Reduction ◽  
Cerebral Artery Occlusion ◽  
Iv Tpa

Background and Purpose: Diffusion-weighted imaging-Alberta Stroke Programme Early CT Score (DWI-ASPECTS) has been associated with short-term and long-term neurological recovery and outcome in acute stroke patients treated with intravenous tissue plasminogen activator (IV-tPA). However, previous reports did not analyze the DW-ASPECTS based on the presence of major arterial occlusion. We investigated whether initial DWI-ASPECTS can predict the short-term neurological recovery in acute stroke patients with the middle cerebral artery occlusion (MCAO) treated with IV t-PA. Methods: Consecutive acute stroke patients with MCAO treated with IV t-PA within 3 hours of onset were enrolled from 2005 October to 2011 May. All patients were examined using DWI and magnetic resonance angiography on admission. Only patients with horizontal MCAO were included. Neurological deficits were assessed using National Institutes of Health Stroke Scale (NIHSS) score on admission and day 7. On day 7, dramatic recovery (DR) was defined as a ≥10 point reduction or a total NIHSS score of 0 or 1. Good recovery (GR) was a ≥4 point reduction, excluding DR. Worsening was a ≥4 point increase. Results: Seventy-one patients (median age [quartiles]; 77 [70-83], male; 44 [62%]) were enrolled into the study. The median NIHSS score was 18 (12-22). The median DWI-ASPECTS was 4 (6-9). Median DWI-ASPECTS was 7 (6-9) in 27 patients with DR group, 5 (4-9) in 13 with GR group, and 3 (2-6) in 17 with worsening (p<0.001). Median DWI-ASPECTS was 4 (3-6) in 4 (6%) patients with type2-parencymal hematoma within 7 days. Using ROC curve, the optimal cut-off DWI-ASPECTS to differentiate DR group from others was >5 (sensitivity of 85% and specificity of 57%, area under curve [AUC] 0.692, p=0.007), and that for worsening group was <4 (sensitivity of 96% and specificity of 59%, AUC 0.785, p<0.001). Multivariate regression analysis demonstrated that initial DWI-ASPECTS of >5 was significantly associated with DR (OR 9.75, 95%CI 1.41-67.67, p=0.021), and <4 with worsening (OR 15.94, 95%CI 4.01-63.25, p<0.001). Conclusion: DWI-ASPECTS can predict the short-term outcome in acute stroke patients with MCAO treated with IV-tPA.

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