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 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

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.

scholarly journals Ermin deficiency as an inside-out model of inflammatory dysmyelination

2020 ◽  
Author(s):  
Amin Ziaei ◽  
Marta Garcia-Miralles ◽  
Carola I. Radulescu ◽  
Harwin Sidik ◽  
Aymeric Silvin ◽  
...  
Keyword(s):  
White Matter ◽  
Critical Role ◽  
Neurological Deficits ◽  
Actin Binding ◽  
New Paradigm ◽  
Conduction Loss ◽  
Myelin Sheaths ◽  
Multiple Sclerosis Patients ◽  
Inside Out

ABSTRACTErmin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling “inside-out” model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies.

Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model

2002 ◽  
Vol 92 (1) ◽  
pp. 195-201 ◽  
Author(s):  
Shao-Hua Yang ◽  
Evelyn Perez ◽  
Jason Cutright ◽  
Ran Liu ◽  
Zhen He ◽  
...  
Keyword(s):  
Sex Differences ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Male Rats ◽  
Neurological Injury ◽  
In Vivo Studies ◽  
Lesion Volume ◽  
Ischemic Lesion

Increasing evidence has demonstrated striking sex differences in the outcome of neurological injury. Whereas estrogens contribute to these differences by attenuating neurotoxicity and ischemia-reperfusion injury, the effects of testosterone are unclear. The present study was undertaken to determine the effects of testosterone on neuronal injury in both a cell-culture model and a rodent ischemia-reperfusion model. Glutamate-induced HT-22 cell-death model was used to evaluate the effects of testosterone on cell survival. Testosterone was shown to significantly increase the toxicity of glutamate at a 10 μM concentration, whereas 17β-estradiol significantly attenuated the toxicity at the same concentration. In a rodent stroke model, ischemia-reperfusion injury was induced by temporal middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. To avoid the stress-related testosterone reduction, male rats were castrated and testosterone was replaced by testosterone pellet implantation. Testosterone pellets were removed at 1, 2, 4, or 6 h before MCAO to determine the duration of acute testosterone depletion effects on infarct volume. Ischemic lesion volume was significantly decreased from 239.6 ± 25.9 mm3 in control to 122.5 ± 28.6 mm3 when testosterone pellets were removed at 6 h before MCAO. Reduction of lesion volume was associated with amelioration of the hyperemia during reperfusion. Our in vitro and in vivo studies suggest that sex differences in response to brain injury are partly due to the consequence of damaging effects of testosterone.

Abstract P317: White Matter Hyperintensity Lesion Burden Modulates Functional Outcome After Acute Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Anna K Bonkhoff ◽  
Sungmin Hong ◽  
Markus Schirmer ◽  
Martin Bretzner ◽  
Anne-Katrin Giese ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
White Matter Hyperintensity ◽  
Study Cohort ◽  
Stroke Severity ◽  
Ischemic Lesion ◽  
Long Term Outcome ◽  
Index Stroke

Introduction: As a radiographic signature of end-stage small vessel disease, white matter hyperintensity (WMH) burden impacts recovery and outcomes after acute ischemic stroke (AIS). In this study, we sought to investigate the effect of WMH volume (WMHv) on stroke severity and functional outcomes independent of the infarct size and topography. Methods: We analyzed 503 AIS patients with MRI data obtained on admission for index stroke enrolled in the multi-center MRI-GENIE study (cohort 1), followed by validation of the findings in an independent single-site study of 555 AIS patients (cohort 2). Stroke severity (NIHSS score) at index stroke and the long-term outcome (3-6 months mRS score) were modeled via Bayesian linear regression. Models included WMHv, age, sex, a 10-dimensional spatial ischemic lesion representation, acute infarct (DWI) volume, and common vascular risk factors (hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease). Results: Cohorts did not differ significantly in major clinical characteristics [cohort 1: age: 65.0±14.6, 41% female, NIHSS: 5.5±5.4, mRS: 1(iqr 2); cohort 2: age: 65.0±14.8, 38% female, NIHSS: 5.0±6.0, mRS: 1(iqr 3), p >0.05 for all comparisons]. WMHv did not substantially affect AIS severity ( Fig A ); in contrast, it emerged as an independent predictor of functional outcome in both datasets ( Fig B ). Conclusions: When accounted for AIS lesion topography and stroke volume, total WMH lesion burden did not appear to modulate initial stroke severity but was associated with worse functional post-stroke outcomes. Future studies are needed to explore potential origins of these detrimental effects of pre-existing WMH burden on recovery after AIS.

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.

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 Posttreatment Ischemic Lesion Evolution Is Associated With Reduced Favorable Functional Outcome in Patients With Stroke

Stroke ◽  
2021 ◽  
Author(s):  
Praneeta Konduri ◽  
Henk van Voorst ◽  
Amber Bucker ◽  
Katinka van Kranendonk ◽  
Anna Boers ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Odds Ratio ◽  
Interaction Analysis ◽  
Univariate Analysis ◽  
Arterial Occlusion ◽  
Lesion Volume ◽  
Ischemic Lesion ◽  
Favorable Functional Outcome

Background and Purpose: Ischemic lesion volume can increase even 24 hours after onset of an acute ischemic stroke. In this study, we investigated the association of lesion evolution with functional outcome and the influence of successful recanalization on this association. Methods: We included patients from the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) who received good quality noncontrast CT images 24 hours and 1 week after stroke onset. The ischemic lesion delineations included infarct, edema, and hemorrhagic transformation. Lesion evolution was defined as the difference between the volumes measured on the 1-week and 24-hour noncontrast CTs. The association of lesion evolution with functional outcome was evaluated using unadjusted and adjusted logistic regression. Adjustments were made for baseline, clinical, and imaging parameters that were associated P <0.10) in univariate analysis with favorable functional outcome, defined as modified Rankin Scale score of ≤2. Interaction analysis was performed to evaluate the influence of successful recanalization, defined as modified Arterial Occlusion Lesion score of 3 points, on this association. Results: Of the 226 patients who were included, 69 (31%) patients achieved the favorable functional outcome. Median lesion evolution was 22 (interquartile range, 10–45) mL. Lesion evolution was significantly inversely correlated with favourable functional outcome: unadjusted odds ratio, 0.76 (95% CI, 0.66–0.86; per 10 mL of lesion evolution; P <0.01) and adjusted odds ratio: 0.85 (95% CI, 0.72–0.97; per 10 mL of lesion evolution; P =0.03). There was no significant interaction of successful recanalization on the association of lesion evolution and favorable functional outcome (odds ratio, 1.01 [95% CI, 0.77–1.36]; P =0.94). Conclusions: In our population, subacute ischemic lesion evolution is associated with unfavorable functional outcome. This study suggests that even 24 hours after onset of stroke, deterioration of the brain continues, which has a negative effect on functional outcome. This finding may warrant additional treatment in the subacute phase.

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