Abstract WMP38: ABCA1/HDL Pathway Mediates GW3965 Induced Neurorestoration and White Matter Remodeling After Stroke

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Xu Cui ◽  
Jieli Chen ◽  
Alex Zacharek ◽  
Yisheng Cui ◽  
Cynthia Roberts ◽  
...  
Keyword(s):  
White Matter ◽  
Functional Outcome ◽  
Cortical Neurons ◽  
Growth Factor Receptor ◽  
Hdl Cholesterol ◽  
Blood Levels ◽  
Oligodendrocyte Progenitor Cells ◽  
Lesion Volume ◽  
Ischemic Brain ◽  
B Mice

ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transporter in the central nervous system, plays an important role in the formation of brain HDL-cholesterol. ABCA1 is up-regulated by the transcription factors, liver X receptors (LXRs). Our previous study using brain-specific ABCA1 deficient (floxed, nestin-Cre positive, ABCA1-B/-B) and ABCA1 floxed-control (ABCA1fl/fl) mice showed that ABCA1 has anti-inflammatory effects and reduces white matter (WM) damage in ischemic stroke models. Here, we further test whether GW3965, a synthetic LXR agonist treatment of stroke increases ABCA1 and HDL, and thereby improves WM-remodeling and functional outcome. Adult male ABCA1fl/fl and ABCA1-B/-B mice were subjected to permanent extraluminal distal middle cerebral artery occlusion (dMCAo) by transcranial ligation method. Animals were gavaged with saline or GW3965 (10 mg/kg) starting 24h after dMCAo and daily till sacrificed 14 days after dMCAo. There were no differences in the lesion volume and blood levels of total cholesterol and triglyceride before and after dMCAo between ABCA1-B/-B and ABCA1fl/fl mice. However, GW3965 treatment significantly increased blood HDL levels in ABCA1fl/fl mice, but not in ABCA1-B/-B mice 14 days after dMCAo. GW3965 treatment of ABCA1fl/fl stroke mice, but not in ABCA1-B/-B stroke mice, also increased: 1) WM-density identified by Luxol Fast Blue (myelin marker), Bielshowsky silver (axon marker), and SMI31 (phosphorylated neurofilament marker) staining; 2) the number of platelet-derived growth factor receptor alpha positive oligodendrocyte progenitor cells; 3) ABCA1, synaptophysin and myelin basic protein expression in the ischemic brain; 4) functional outcome 7 and 14 days after dMCAo, compared with non-treatment ABCA1fl/fl stroke mice (p<0.05, n=9/group). GW3965 and HDL treatment significantly increase axonal/neurite outgrowth in cultured primary cortical neurons derived from ABCA1fl/fl embryos, but not in neurons derived from ABCA1-B/-B embryos. Treatment of stroke with GW3965 significantly increased blood level of HDL, increased ABCA1 expression and WM-remodeling in the ischemic brain. Increasing ABCA1 may contribute to GW3965 induced neurorestoration and WM remodeling after stroke.

Abstract W MP38: Apolipoprotein A-I (ApoA-I) Mimetic Peptide, D-4F, Regulates miRNA Expression and Improves Functional Outcome after Stroke in Diabetic Rats

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Ruizhuo Ning ◽  
Michael Chopp ◽  
Alex Zacharek ◽  
Tao Yan ◽  
Cynthia Roberts ◽  
...  
Keyword(s):  
Functional Outcome ◽  
Mirna Expression ◽  
Target Gene ◽  
M2 Macrophage ◽  
Lesion Volume ◽  
Ischemic Brain ◽  
Mimetic Peptide ◽  
Hdl Function ◽  
Functional Benefit ◽  
Gene And Protein Expression

Introduction: Diabetes mellitus (DM) in patients is associated with low high-density lipoprotein cholesterol (HDL-C) and impairment of the anti-oxidative capacity of HDL-C. Several miRNAs have been identified as having a physiological role in tissues in which diabetes complications occur. D-4F is an economical ApoA-I mimetic peptide which increases HDL function. We therefore investigated the therapeutic effect and underlying mechanisms of D-4F treatment of stroke induced functional benefit effects in type one DM (T1DM) rats. Methods: T1DM was induced in Wistar rats by streptozotocin (60mg/kg, ip) .Subsequently they were subjected to embolic middle cerebral artery occlusion. D-4F (10 mg/kg i.p.) was administered at 2h, 24h and 48h after stroke. Functional outcomes, brain blood barrier (BBB) leakage and lesion volume were evaluated. Results: D-4F treatment of stroke in T1DM rats significantly decreased Evans Blue dye leakage (15.85±1.52 ng/mg vs contro: 30.57± 5.88 ng/mg) and significantly improved functional outcome compared to non-treatment T1DM-control. D-4F treatment significantly increased miR-124a and miR-181c, but decreased miR-200b expression in the ischemic brain. Using laser capture, D-4F also significantly increased ischemic brain endothelial cell miR-126 expression compared to non-treatment control. In addition, D-4F treatment significantly decreased miR-181c target gene tumor necrosis factor-a (TNF-a), and miR-124a target gene monocyte chemoattractant protein-1 (MCP1) expression. D-4F also decreased proinflammatory nuclear NFkB (26.07±3.17 vs 37.43±3.47), Toll-like receptor 4 (TLR4, 7.26±0.69 vs 10.5±1.2), matrix metalloproteinase 9 (MMP9, 0.16±0.04 vs 0.48±0.09) expression, and increased CD163 (M2 macrophage marker, 120.98±8.13 vs 85.02± 9.47) number compared to T1DM-MCAo control rats. Conclusion: D-4F treatment of stroke in T1DM rats regulates miRNA expression and their target gene and protein expression and induces anti-inflammatory effects and promotes M2 macrophage polarization which may contribute to D-4F decreased BBB leakage and induced functional benefit effects after stroke in T1DM rats.

scholarly journals Long Noncoding RNA Fos Downstream Transcript Is Developmentally Dispensable but Vital for Shaping the Poststroke Functional Outcome

Stroke ◽  
2021 ◽  
Author(s):  
Suresh L. Mehta ◽  
Anil K. Chokkalla ◽  
TaeHee Kim ◽  
Saivenkateshkomal Bathula ◽  
Bharath Chelluboina ◽  
...  
Keyword(s):  
Functional Outcome ◽  
Rna Sequencing ◽  
Brain Damage ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Focal Ischemia ◽  
Developmental Expression ◽  
Lesion Volume ◽  
Sequencing Analysis ◽  
Ischemic Brain

Background and Purpose: Stroke induces the expression of several long noncoding RNAs in the brain. However, their functional significance in poststroke outcome is poorly understood. We recently observed that a brain-specific long noncoding RNA called Fos downstream transcript (FosDT) is induced rapidly in the rodent brain following focal ischemia. Using FosDT knockout rats, we presently evaluated the role of FosDT in poststroke brain damage. Methods: FosDT knockout rats were generated using CRISPR-Cas9 genome editing on a Sprague-Dawley background. Male and female FosDT −/− and FosDT +/+ cohorts were subjected to transient middle cerebral artery occlusion. Postischemic sensorimotor deficits were evaluated between days 1 and 7 and lesion volume on day 7 of reperfusion. The developmental expression profile of FosDT was determined with real-time polymerase chain reaction and mechanistic implications of FosDT in the ischemic brain were conducted with RNA-sequencing analysis and immunostaining of pathological markers. Results: FosDT expression is developmentally regulated, with the adult cerebral cortex showing significantly higher FosDT expression than neonates. FosDT −/− rats did not show any anomalies in growth and development, fertility, brain cytoarchitecture, and cerebral vasculature. However, when subjected to transient focal ischemia, FosDT −/− rats of both sexes showed enhanced sensorimotor recovery and reduced brain damage. RNA-sequencing analysis showed that improved poststroke functional outcome in FosDT −/− rats is partially associated with curtailed induction of inflammatory genes, reduced apoptosis, mitochondrial dysfunction, and oxidative stress. Conclusions: Our study shows that FosDT is developmentally dispensable, mechanistically important, and a functionally promising target to reduce ischemic brain damage and facilitate neurological recovery.

Abstract WP103: ABCA1/HDL Signaling Pathway Mediates White Matter Remodeling and Improves Functional Outcome After Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Rongwen Li ◽  
Michael Chopp ◽  
Jieli Chen ◽  
Alex Zacharek ◽  
fengjie Wang ◽  
...  
Keyword(s):  
White Matter ◽  
Functional Outcome ◽  
Critical Role ◽  
Conditioned Media ◽  
Neurological Deficits ◽  
Control Treatment ◽  
Axonal Outgrowth ◽  
Lesion Volume ◽  
Ischemic Lesion

The ATP-binding cassette transporter A1 (ABCA1) plays a critical role in the formation of brain HDL cholesterol, mainly from astrocytes. Specific brain ABCA1 deficient (ABCA1 -B/-B ) mice exhibit reduced HDL levels in brain tissue and cerebrospinal fluid, as well as increases in white matter (WM) damage and neurological deficits after stroke. We tested the hypothesis, that treatment of stroke in ABCA1 -B/-B mice with intraventricularly infused HDL increases WM remodeling in the ischemic brain and attenuates ABCA1 -B/-B induced deficits after stroke. Method: Adult male ABCA1 -B/-B mice were subjected to permanent right distal middle cerebral artery occlusion (dMCAo), and were intraventricularly infused with PBS or recombinant human HDL3 (rhHDL3, 25μg in 100μl PBS) by transplanting a micro-osmotic pump (D1002, 0.25 μl/h for 14 days, Alzet) into the right lateral ventricle starting 24h after dMCAo. Animals were sacrificed 21 days after dMCAo. In vitro primary cortical neuron (PCN) culture derived from C57BL/6 and ABCA1 -B/-B embryos and axonal outgrowth measurements were also employed. Results: 1) There were no ischemic lesion volume changes between the two groups. 2) rhHDL3-infused ABCA1 -B/-B stroke mice exhibited significantly increased WM-remodeling identified by increased level of myelin basic protein, increased densities of myelin and axons, increased number of oligodendrocytes and oligodendrocyte progenitor cells in the ischemic boundary zone, as well as improved functional outcome compared with PBS-infused ABCA1 -B/-B stroke mice (p<0.05, n=8/group). 3) HDL (40 or 80μg/ml) treatment in ABCA1 -B/-B -PCNs significantly increased axonal outgrowth compared to non-treatment control. Treatment of C57BL/6-PCNs with astrocyte-conditioned media derived from ABCA1 -B/-B embryos significantly decreased axonal outgrowth compared to treatment with astrocyte-conditioned media derived from ABCA1 floxed-control embryos. However, ABCA1 -B/-B -astrocyte-conditioned media combination with HDL treatment significantly increased C57BL/6-PCN axonal outgrowth compared to treatment with ABCA1 -B/-B -astrocyte-conditioned media alone. Conclusion: ABCA1/HDL pathway may contribute to WM-remodeling as well as functional recovery after stroke.

scholarly journals Administration of Downstream ApoE Attenuates the Adverse Effect of Brain ABCA1 Deficiency on Stroke

2018 ◽  
Vol 19 (11) ◽  
pp. 3368 ◽  
Author(s):  
Xiaohui Wang ◽  
Rongwen Li ◽  
Alex Zacharek ◽  
Julie Landschoot-Ward ◽  
Fengjie Wang ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Cortical Neurons ◽  
Glucose Deprivation ◽  
Vehicle Control ◽  
Cholesterol Homeostasis ◽  
Functional Improvement ◽  
Lesion Volume ◽  
Ischemic Lesion ◽  
Ischemic Brain

The ATP-binding cassette transporter member A1 (ABCA1) and apolipoprotein E (ApoE) are major cholesterol transporters that play important roles in cholesterol homeostasis in the brain. Previous research demonstrated that specific deletion of brain-ABCA1 (ABCA1−B/−B) reduced brain grey matter (GM) and white matter (WM) density in the ischemic brain and decreased functional outcomes after stroke. However, the downstream molecular mechanism underlying brain ABCA1-deficiency-induced deficits after stroke is not fully understood. Adult male ABCA1−B/−B and ABCA1-floxed control mice were subjected to distal middle-cerebral artery occlusion and were intraventricularly infused with artificial mouse cerebrospinal fluid as vehicle control or recombinant human ApoE2 into the ischemic brain starting 24 h after stroke for 14 days. The ApoE/apolipoprotein E receptor 2 (ApoER2)/high-density lipoprotein (HDL) levels and GM/WM remodeling and functional outcome were measured. Although ApoE2 increased brain ApoE/HDL levels and GM/WM density, negligible functional improvement was observed in ABCA1-floxed-stroke mice. ApoE2-administered ABCA1−B/−B stroke mice exhibited elevated levels of brain ApoE/ApoER2/HDL, increased GM/WM density, and neurogenesis in both the ischemic ipsilateral and contralateral brain, as well as improved neurological function compared with the vehicle-control ABCA1−B/−B stroke mice 14 days after stroke. Ischemic lesion volume was not significantly different between the two groups. In vitro supplementation of ApoE2 into primary cortical neurons and primary oligodendrocyte-progenitor cells (OPCs) significantly increased ApoER2 expression and enhanced cholesterol uptake. ApoE2 promoted neurite outgrowth after oxygen-glucose deprivation and axonal outgrowth of neurons, and increased proliferation/survival of OPCs derived from ABCA1−B/−B mice. Our data indicate that administration of ApoE2 minimizes the adverse effects of ABCA1 deficiency after stroke, at least partially by promoting cholesterol traffic/redistribution and GM/WM remodeling via increasing the ApoE/HDL/ApoER2 signaling pathway.

scholarly journals Associations between Urinary and Dietary Selenium and Blood Metabolic Parameters in a Healthy Northern Italy Population

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1193
Author(s):  
Teresa Urbano ◽  
Tommaso Filippini ◽  
Daniela Lasagni ◽  
Tiziana De Luca ◽  
Sabrina Sucato ◽  
...  
Keyword(s):  
Linear Regression Analysis ◽  
Positive Association ◽  
Hdl Cholesterol ◽  
Thyroid Stimulating Hormone ◽  
Blood Levels ◽  
Dietary Selenium ◽  
Selenium Intake ◽  
Glucose Levels ◽  
Beta Coefficient ◽  
Essential Nutrient

Selenium is both an essential nutrient and a highly toxic element, depending on its dose and chemical forms. We aimed to quantify urinary selenium excretion and dietary selenium intake in 137 healthy non-smoking blood donors living in the northern Italian province of Reggio Emilia. We assessed selenium status by determining urinary selenium levels (mean 26.77 µg/L), and by estimating dietary selenium intake (mean 84.09 µg/day) using a validated semi-quantitative food frequency questionnaire. Fasting blood levels of glucose, lipids and thyroid-stimulating hormone were measured using automatized laboratory procedures. Dietary and urinary selenium were correlated (beta coefficient (β) = 0.19). Despite this, the association of the two indicators with health endpoints tended to diverge. Using linear regression analysis adjusted for age, sex, body mass index, cotinine levels and alcohol intake, we observed a positive association between urinary selenium and blood triglyceride (β = 0.14), LDL-cholesterol (β = 0.07) and glucose levels (β = 0.08), and an inverse one with HDL-cholesterol (β = −0.12). Concerning dietary selenium, a slightly positive association could be found with glycemic levels only (β = 0.02), while a negative one emerged for other endpoints. The two selenium indicators showed conflicting and statistically highly imprecise associations with circulating TSH levels. Our findings suggest that higher selenium exposure is adversely associated with blood glucose levels and lipid profile. This is the case even at selenium exposures not exceeding tolerable upper intake levels according to current guidelines.

scholarly journals Effects of post-interventional antiplatelet therapy on angiographic vasospasm, delayed cerebral ischemia, and clinical outcome after aneurysmal subarachnoid hemorrhage: a single-center experience

2021 ◽  
Author(s):  
Claudia Ditz ◽  
Björn Machner ◽  
Hannes Schacht ◽  
Alexander Neumann ◽  
Peter Schramm ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Functional Outcome ◽  
Antiplatelet Therapy ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Control Group ◽  
Lesion Volume ◽  
Single Center ◽  
Single Center Experience

AbstractPlatelet activation has been postulated to be involved in the pathogenesis of delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to investigate potentially beneficial effects of antiplatelet therapy (APT) on angiographic CVS, DCI-related infarction and functional outcome in endovascularly treated aSAH patients. Retrospective single-center analysis of aSAH patients treated by endovascular aneurysm obliteration. Based on the post-interventional medical regime, patients were assigned to either an APT group or a control group not receiving APT. A subgroup analysis separately investigated those APT patients with aspirin monotherapy (MAPT) and those receiving dual treatment (aspirin plus clopidogrel, DAPT). Clinical and radiological characteristics were compared between groups. Possible predictors for angiographic CVS, DCI-related infarction, and an unfavorable functional outcome (modified Rankin scale ≥ 3) were analyzed. Of 160 patients, 85 (53%) had received APT (n = 29 MAPT, n = 56 DAPT). APT was independently associated with a lower incidence of an unfavorable functional outcome (OR 0.40 [0.19–0.87], P = 0.021) after 3 months. APT did not reduce the incidence of angiographic CVS or DCI-related infarction. The pattern of angiographic CVS or DCI-related infarction as well as the rate of intracranial hemorrhage did not differ between groups. However, the lesion volume of DCI-related infarctions was significantly reduced in the DAPT subgroup (P = 0.011). Post-interventional APT in endovascularly treated aSAH patients is associated with better functional outcome at 3 months. The beneficial effect of APT might be mediated by reduction of the size of DCI-related infarctions.

scholarly journals Associations of Ischemic Lesion Volume With Functional Outcome in Patients With Acute Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (5) ◽  
pp. 1233-1240 ◽  
Author(s):  
Amber Bucker ◽  
Anna M. Boers ◽  
Joseph C.J. Bot ◽  
Olvert A. Berkhemer ◽  
Hester F. Lingsma ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Lesion Volume ◽  
Ischemic Lesion

scholarly journals How a common variant in the growth factor receptor gene,NTRK1, affects white matter

2012 ◽  
Vol 2 (5) ◽  
pp. 181-184 ◽  
Author(s):  
Meredith N. Braskie ◽  
Neda Jahanshad ◽  
Arthur W. Toga ◽  
Katie L. McMahon ◽  
Greig I. de Zubicaray ◽  
...  
Keyword(s):  
White Matter ◽  
Growth Factor ◽  
Receptor Gene ◽  
Growth Factor Receptor ◽  
Common Variant

scholarly journals Automated White Matter Total Lesion Volume Segmentation in Diabetes

2013 ◽  
Vol 34 (12) ◽  
pp. 2265-2270 ◽  
Author(s):  
J.A. Maldjian ◽  
C.T. Whitlow ◽  
B.N. Saha ◽  
G. Kota ◽  
C. Vandergriff ◽  
...  
Keyword(s):  
White Matter ◽  
Lesion Volume ◽  
Volume Segmentation

Abstract W MP87: PDGF Contributes to BMSC Treatment Induced Neurogenesis and White Matter and Axonal Remodeling in T2DM Stroke Rats

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Alex Zacharek ◽  
Tao Yan ◽  
Michael Chopp` ◽  
Poornima Venkat ◽  
Ruizhou Ning ◽  
...  
Keyword(s):  
Cell Migration ◽  
White Matter ◽  
Artery Occlusion ◽  
Border Zone ◽  
Axonal Outgrowth ◽  
Ischemic Brain ◽  
Neuroblast Migration ◽  
Gene And Protein Expression ◽  
Underlying Mechanisms

Objective: Our previous studies have found that bone-marrow-stromal cell (BMSC) treatment of stroke in Type two DM (T2DM) rats, initiated at 3 days after stroke, improved functional recovery. Neurogenesis and white matter (WM) remodeling play an important role in neurorestorative effects after stroke. In this study, we tested whether BMSCs regulate neurogenesis and WM remodeling and the underlying mechanisms of BMSC induced neurorestorative effects in T2DM stroke rats. Methods: T2DM was induced with streptozotocin injection in addition to a high fat diet. T2DM rats were subjected to 2h of middle cerebral artery occlusion (MCAo), then treated with human BMSCs (5X106) or vehicle control (n=8/group) initiated at 3 days after MCAo and rats were monitored for 28 days. Neuroblast migration, WM changes, and gene and protein expression were measured in the ischemic brain. Subventricular zone (SVZ) explant cell migration and primary cortical neuron (PCN) axonal outgrowth measurements were performed in vitro. Results: BMSC treatment in T2DM rats significantly improves functional outcome and increases WM remodeling identified by increased myelin and axonal density. BMSCs also increase the neuroblast migration protein doublecortin (DCX, 25.0±4.3% vs control: 4.5±1.1%), platelet-derived growth factor (PDGF)-AA, and bFGF expression in the ischemic border zone. Angiogenic ELISA array data are consistent with the immunostaining data, showing that BMSC treatment increases PDGF-AA (2.1 fold), PDGF-BB (2.5 fold) and bFGF (1.8 fold) in the ischemic brain. Using an in vitro cell culture model, we found that BMSCs secrete high levels of PDGF. PDGF treatment significantly increases SVZ explant cell migration (1.7 fold) and PCN axonal outgrowth (1.9 fold) compared to non-treatment control. Inhibition of PDGF with neutralized anti-PDGF antibody significantly attenuates BMSC conditioned medium induced SVZ cell migration and PCN axon outgrowth. Conclusion: BMSC treatment of stroke in T2DM increases WM remodeling and neurogenesis as well as increases PDGF expression. PDGF not only promotes neuronal migration, but also increases axonal outgrowth. Therefore, increasing PDGF likely contributes to BMSC induced neurogenesis and WM remodeling in T2DM stroke rats.

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