scholarly journals GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice

2017 ◽  
Vol 39 (1) ◽  
pp. 74-88 ◽  
Author(s):  
Maria EK Lie ◽  
Emma K Gowing ◽  
Nina B Johansen ◽  
Nils Ole Dalby ◽  
Louise Thiesen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Surface Expression ◽  
Tonic Inhibition ◽  
Stroke Recovery ◽  
Gaba Uptake ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Post Stroke ◽  
Long Term Treatment

Ischemic stroke triggers an elevation in tonic GABA inhibition that impairs the ability of the brain to form new structural and functional cortical circuits required for recovery. This stroke-induced increase in tonic inhibition is caused by impaired GABA uptake via the glial GABA transporter GAT3, highlighting GAT3 as a novel target in stroke recovery. Using a photothrombotic stroke mouse model, we show that GAT3 protein levels are decreased in peri-infarct tissue from 6 h to 42 days post-stroke. Prior studies have shown that GAT substrates can increase GAT surface expression. Therefore, we aimed to assess whether the GAT3 substrate, L-isoserine, could increase post-stroke functional recovery. L-Isoserine (38 µM or 380 µM) administered directly into the infarct from day 5 to 32 post-stroke, significantly increased motor performance in the grid-walking and cylinder tasks in a concentration-dependent manner, without affecting infarct volumes. Additionally, L-isoserine induced a lasting increase in GAT3 expression in peri-infarct regions accompanied by a small decrease in GFAP expression. This study is the first to show that a GAT3 substrate can increase GAT3 expression and functional recovery after focal ischemic stroke following a delayed long-term treatment. We propose that enhancing GAT3-mediated uptake dampens tonic inhibition and promotes functional recovery after stroke.

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.

Abstract WP105: Tissue Plasminogen Activator (tPA) is Essential for Functional Recovery After Stroke by Promoting Axonal Outgrowth

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Shubei Ma
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Recovery ◽  
Stroke Recovery ◽  
White Matter Integrity ◽  
Blue Staining ◽  
Tissue Plasminogen

Objectives: Stroke is the leading cause of long term neurological disability with limited therapeutic options. Human recombinant tissue plasminogen activator (tPA) is currently the only FDA approved drug for the thrombolytic treatment of ischemic stroke. Emerging evidence suggests that the effects of tPA in ischemic brain may extend beyond its thrombolytic activity. In this study, we investigated the role of tPA in long term stroke recovery. Methods: Cortical infarct was induced by distal middle cerebral artery occlusion (dMCAO) in tPA knockout (KO) and wild type (WT) mice. Sensorimotor functions were evaluated at 3-35 days after dMCAO. White matter integrity was assessed by luxol fast blue staining, immunohistochemistry for SMI-32, and diffusion tensor imaging (DTI). The neuronal tracer biotinylated dextran amine (BDA) was used to label the corticorubral tract and the corticospinal tract. For rescue experiment, tPA (2mg/kg) was delivered intranasally to tPA KO mice once a day for 14 days starting 6h after dMCAO. Results: Infarct volume was comparable between tPA KO and WT mice after dMCAO. Sensorimotor deficits after dMCAO were exacerbated in tPA KO mice than WT mice. tPA KO mice also showed more severe demyelination in post-stroke white matter and reduced axonal sprouting at 35 days after dMCAO compared to WT mice. DTI studies revealed deteriorated white matter integrity in tPA KO mice, as manifested by decreased fractional anisotropy. Intranasal delivery of tPA after dMCAO rescued the neurological phenotype shown by tPA KO mice. Conclusion: Endogenous tPA promotes white matter integrity and is essential for functional recovery after ischemic stroke. tPA may be a novel neurorestorative therapy for stroke recovery.

scholarly journals Role of P-selectin and leukocyte activation in polymorphonuclear cell adhesion to surface adherent activated platelets under physiologic shear conditions (an injury vessel wall model)

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2498-2507 ◽  
Author(s):  
EL Yeo ◽  
JA Sheppard ◽  
IA Feuerstein
Keyword(s):  
Flow Cytometric Analysis ◽  
Surface Expression ◽  
Metabolic Inhibitor ◽  
Dependent Manner ◽  
Polymorphonuclear Cell ◽  
Concentration Dependent Manner ◽  
Binding Condition ◽  
Activated Platelets ◽  
Platelet Binding

Abstract Carbohydrate moieties on leukocytes adhere to activated platelets via P- selectin under static binding condition studies. We characterize polymorphonuclear cell (PMN) surface interactions with surface adherent platelets and the PMNs response, under physiologic flow conditions corresponding to a shear of 100 s-1, in an in vitro flow chamber. Fluorescent labeled PMNs with red blood cells were drawn through a transparent flow channel and visually quantitated over 30 minutes, interacting with a confluent monolayer of activated, shear-spread platelets expressing P-selectin. PMN adhesion was saturable (2,250 +/- 350/mm2), and time and cation (Ca2+, Mg2+) dependent, and PMNs did not bind to the experimental surface in the absence of a platelet monolayer. P-selectin antibodies completely abolished PMN adhesion in a concentration-dependent manner with half inhibition at 70 micrograms/mL. Antibodies to a putative P-selectin receptor CD15 (80H5 and MMA) maximally inhibited PMN adhesion by 73% and 10%, respectively. Adherent PMNs appeared morphologically activated and flow cytometric analysis of adherent PMNs confirmed activation because CD11b and CD18 surface expression was upregulated (100% and 27%, respectively), whereas L-selectin was downregulated (55%) compared with control nonadherent PMNs. In the presence of the metabolic inhibitor sodium azide (0.02% and 0.1%) there was a 23% +/- 9% and 51% +/- 3% decrease, respectively, in PMN adhesion at 100 s-1. Thus, P-selectin is required for PMN adhesion to a pathophysiologic surface of activated adherent platelets at physiologic shear rates. Furthermore, a secondary step involving PMN activation after platelet binding appears necessary for complete (irreversible) adhesion to occur. This unique flow cell provides a model to explore, under controlled conditions, biologic mechanisms and ligands involved in leukocyte-platelet binding that play important roles in PMN localization at sites of thrombosis and vascular injury.

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 Longitudinal Effects of Lesions on Functional Networks after Stroke

2013 ◽  
Vol 33 (8) ◽  
pp. 1279-1285 ◽  
Author(s):  
Smadar Ovadia-Caro ◽  
Kersten Villringer ◽  
Jochen Fiebach ◽  
Gerhard Jan Jungehulsing ◽  
Elke van der Meer ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Resting State ◽  
Large Scale ◽  
Clinical Symptoms ◽  
Resting State Fmri ◽  
Functional Change ◽  
Stroke Recovery ◽  
Focal Lesion ◽  
Supporting Evidence ◽  
Post Stroke

While ischemic stroke reflects focal damage determined by the affected vascular territory, clinical symptoms are often more complex and may be better explained by additional indirect effects of the focal lesion. Assumed to be structurally underpinned by anatomical connections, supporting evidence has been found using alterations in the functional connectivity of resting-state functional magnetic resonance imaging (fMRI) data in both sensorimotor and attention networks. To assess the generalizability of this phenomenon in a stroke population with heterogeneous lesions, we investigated the distal effects of lesions on a global level. Longitudinal resting-state fMRI scans were acquired at three consecutive time points, beginning during the acute phase (days 1, 7, and 90 post-stroke) in 12 patients after ischemic stroke. We found a preferential functional change in affected networks (i.e., networks containing lesions changed more during recovery when compared with unaffected networks). This change in connectivity was significantly correlated with clinical changes assessed with the National Institute of Health Stroke Scale. Our results provide evidence that the functional architecture of large-scale networks is critical to understanding the clinical effect and trajectory of post-stroke recovery.

scholarly journals ЗАСТОСУВАННЯ Α-ГЛІЦЕРИЛФОСФОРИЛХОЛІНУ В СХЕМІ КОМПЛЕКСНОГО ЛІКУВАННЯ ДЛЯ ФУНКЦІОНАЛЬНОГО ВІДНОВЛЕННЯ ПІСЛЯ МОЗКОВОГО ПІВКУЛЬОВОГО ІШЕМІЧНОГО ІНСУЛЬТУ

2021 ◽  
Vol 25 (3-4) ◽  
pp. 8-13
Author(s):  
О.О. Пушко ◽  
Н.В. Литвиненко
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Vascular Diseases ◽  
Comprehensive Treatment ◽  
Post Stroke ◽  
Rehabilitation Programs ◽  
Comprehensive Therapy ◽  
Progressive Growth ◽  
Active Rehabilitation ◽  
Combination Of Methods

The article considers the influence of α-glycerylphosphorylcholine in the scheme of comprehensive therapy on the dynamics of functional recovery in patients with cerebral hemispheric ischemic stroke. Against the background of the progressive growth of acute cerebral infarction, the problem of timely care is relevant. Timely treatment of stroke, based on evidence-based medicine, along with early activation and rehabilitation of patients is designed to reduce mortality and subsequent disability of patients. Given that cholinergic insufficiency and structural and functional damage of neurons play an important role in the pathogenesis of post-stroke disorders, the use of medicines for their correction, in particular α-glycerylphosphorylcholine, is justified. Choline alfoscerate, a precursor of acetylcholine and phosphatidylcholine, is broken down by enzymes into choline and glycerophosphate when ingested, and the choline thus obtained is able to improve neuronal functionality in patients with neurodegenerative and vascular diseases. The study revealed a significantly better recovery of impaired motor and cognitive functions after cerebral hemispheric stroke under the influence of comprehensive therapeutic and rehabilitation measures using active rehabilitation methods in conjunction with α-glycerylphosphorylcholine. The results obtained during the study allow us to report the advantage of a combination of methods of active rehabilitation and the use of the pharmacological agent α-glycerylphosphorylcholine. The feasibility and efficacy of α-glycerylphosphorylcholine are related to its ability to reduce motor and cognitive deficits after ischemic stroke. The scheme of comprehensive treatment of patients in acute and restorative periods of cerebral hemispheric ischemic stroke with the use of α-glycerylphosphorylcholine helps to increase the effectiveness of functional recovery after an acute cerebral accident, and can be used in the use of therapeutic and rehabilitation programs for patients after cerebral hemispheric ischemic stroke to reduce the post-stroke deficit.

Abstract 3133: Impact of Post-stroke Isolation on Stroke Outcome

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Venugopal R Venna ◽  
Yan Xu ◽  
Jun Li ◽  
Fudong Liu ◽  
Louise D McCullough
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Forced Swim Test ◽  
Statistical Significance ◽  
Experimental Studies ◽  
Stroke Recovery ◽  
Stroke Outcome ◽  
Post Stroke ◽  
The Impact

Background: Psychosocial factors are increasingly accepted as critical factors in post-stroke recovery, mortality and morbidity. Although, emerging data from clinical and population based studies support the role of social support in improved functional recovery and reducing the risk of mortality, to date no experimental studies have investigated such effects in post-stroke animal models. The aim of this study is to investigate for the impact of post stroke housing and the effects of long-term social isolation and pair housing with either a healthy or a stroked partner, and explored for the mechanisms. Methods: Male mice (20-25g; C57BL/6N, Charles River Labs), all initially pair housed, were subjected to right middle cerebral artery occlusion (MCAO - 60min) and then randomly assigned to a specific housing condition - isolated, paired with a stroke partner or paired with a healthy partner. Infarct size was quantified with TTC 72h after stroke (n=8/grp). We then investigated the effects of housing on long-term functional recovery using corner test, cylinder test, forced swim test (FST) and tail suspension test (TST). We further explored the mechanisms underlying the improved behavioral recovery by injecting BrDU 150mg/kg/day i.p. for 5 days starting from day 3 post-stroke (n=8/grp), and assessing changes in BDNF levels by western-blot analysis (n=4/grp). Data were expressed as mean±sem. Two-way ANOVA was performed and P value < .05 was set for statistical significance. Results: Post-stroke housing conditions can significantly impact infarct size; we observed that mice isolated after stroke had increased infarct volume compared to pair housed mice in all three brain regions (Cortex: 63.2±2.5 vs 40.0±6.2; p<0.01); (Striatum: 86.6±2.2 vs 67.7±2.9; p<0.01); (Total: 60.9±1.3 vs 32.6±4.3; p<0.01). Although post-stroke housing with healthy vs a stroked partner did not influenced infarct size (p>0.05), animals pair housed with healthy partner showed a significantly improved functional recovery by as early as day 15 in the cylinder and corner tests (p<0.05). Increased mobility was observed in FST and TST in PH mice compared to SI mice at day 90 (p<0.05). Consistently, housing with a healthy partner increased BrDU positive cells (p<0.05) and enhanced BDNF expression compared to other cohorts (SI 1±0.1; PH with stroke partner 1.9±0.2; PH with healthy partner 2.6±0.1; n=4/grp), no changes were seen in sham mice. Conclusions: Post-stroke housing has an important impact on stroke outcome; isolation has a detrimental effect on infarct size compared to pair housed cohorts. Interestingly, independent of infarct size, housing with a healthy partner hastened recovery compared to those stroke mice housed with partner that had also been subjected to stroke. Molecular analysis indicates the involvement of BDNF and neurogenesis may be important regulators of post-stroke housing induced functional recovery.

Prolonged release of VEGF and Ang1 from intralesionally implanted hydrogel promotes perilesional vascularization and functional recovery after experimental ischemic stroke

2022 ◽  
pp. 0271678X2110699
Author(s):  
Pavel Yanev ◽  
Geralda AF van Tilborg ◽  
Annette van der Toorn ◽  
Xiangmei Kong ◽  
Ann M Stowe ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Release Kinetics ◽  
Chronic Phase ◽  
Stroke Recovery ◽  
Intralesional Injection ◽  
Prolonged Release ◽  
Post Stroke ◽  
In Situ Forming

Injectable hydrogels can generate and support pro-repair environments in injured tissue. Here we used a slow-releasing drug carrying in situ-forming hydrogel to promote post-stroke recovery in a rat model. Release kinetics were measured in vitro and in vivo with MRI, using gadolinium-labeled albumin (Galbumin), which demonstrated prolonged release over multiple weeks. Subsequently, this hydrogel was used for long-term delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) (Gel VEGF + Ang1, n = 14), in a photothrombotically induced cortical stroke lesion in rats. Control stroke animals were intralesionally injected with saline (Saline, n = 10), non-loaded gel (Gel, n = 10), or a single bolus of VEGF + Ang1 in saline (Saline VEGF + Ang1, n = 10). MRI was executed to guide hydrogel injection. Functional recovery was assessed with sensorimotor function tests, while tissue status and vascularization were monitored by serial in vivo MRI. Significant recovery from sensorimotor deficits from day 28 onwards was only measured in the Gel VEGF + Ang1 group. This was accompanied by significantly increased vascularization in the perilesional cortex. Histology confirmed (re)vascularization and neuronal sparing in perilesional areas. In conclusion, intralesional injection of in situ-forming hydrogel loaded with pro-angiogenic factors can support prolonged brain tissue regeneration and promote functional recovery in the chronic phase post-stroke.

scholarly journals Bovine CD18 Is Necessary and Sufficient To Mediate Mannheimia (Pasteurella) haemolytica Leukotoxin-Induced Cytolysis

2002 ◽  
Vol 70 (9) ◽  
pp. 5058-5064 ◽  
Author(s):  
M. S. Deshpande ◽  
T. C. Ambagala ◽  
A. P. N. Ambagala ◽  
M. E. Kehrli ◽  
S. Srikumaran
Keyword(s):  
Cell Surface ◽  
Surface Expression ◽  
Surface Proteins ◽  
Polymorphonuclear Neutrophils ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Dependent Manner ◽  
Β Subunit ◽  
Concentration Dependent Manner ◽  
Necessary And Sufficient

ABSTRACT Leukotoxin (Lkt) secreted by Mannheimia (Pasteurella) haemolytica is an RTX toxin which is specific for ruminant leukocytes. Lkt binds to β2 integrins on the surface of bovine leukocytes. β2 integrins have a common β subunit, CD18, that associates with three distinct α chains, CD11a, CD11b, and CD11c, to give rise to three different β2 integrins, CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), and CD11c/CD18 (CR4), respectively. Our earlier studies revealed that Lkt binds to all three β2 integrins, suggesting that the common β subunit, CD18, may be the receptor for Lkt. In order to unequivocally elucidate the role of bovine CD18 as a receptor for Lkt, a murine cell line nonsusceptible to Lkt (P815) was transfected with cDNA for bovine CD18. One of the transfectants, 2B2, stably expressed bovine CD18 on the cell surface. The 2B2 transfectant was effectively lysed by Lkt in a concentration-dependent manner, whereas the P815 parent cells were not. Immunoprecipitation of cell surface proteins of 2B2 with monoclonal antibodies specific for bovine CD18 or murine CD11a suggested that bovine CD18 was expressed on the cell surface of 2B2 as a heterodimer with murine CD11a. Expression of bovine CD18 and the Lkt-induced cytotoxicity of 2B2 cells were compared with those of bovine polymorphonuclear neutrophils and lymphocytes. There was a strong correlation between cell surface expression of bovine CD18 and percent cytotoxicity induced by Lkt. These results indicate that bovine CD18 is necessary and sufficient to mediate Lkt-induced cytolysis of target cells.

scholarly journals Strychnine-sensitive glycine receptors on pyramidal neurons in layers II/III of the mouse prefrontal cortex are tonically activated

2014 ◽  
Vol 112 (5) ◽  
pp. 1169-1178 ◽  
Author(s):  
Michael C. Salling ◽  
Neil L. Harrison
Keyword(s):  
Prefrontal Cortex ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Tonic Inhibition ◽  
Dependent Manner ◽  
Glycine Receptors ◽  
Decay Kinetics ◽  
Concentration Dependent Manner ◽  
Inhibitory Neurotransmitter ◽  
Current Shift

Processing of signals within the cerebral cortex requires integration of synaptic inputs and a coordination between excitatory and inhibitory neurotransmission. In addition to the classic form of synaptic inhibition, another important mechanism that can regulate neuronal excitability is tonic inhibition via sustained activation of receptors by ambient levels of inhibitory neurotransmitter, usually GABA. The purpose of this study was to determine whether this occurs in layer II/III pyramidal neurons (PNs) in the prelimbic region of the mouse medial prefrontal cortex (mPFC). We found that these neurons respond to exogenous GABA and to the α4δ-containing GABAA receptor (GABAAR)-selective agonist gaboxadol, consistent with the presence of extrasynaptic GABAAR populations. Spontaneous and miniature synaptic currents were blocked by the GABAAR antagonist gabazine and had fast decay kinetics, consistent with typical synaptic GABAARs. Very few layer II/III neurons showed a baseline current shift in response to gabazine, but almost all showed a current shift (15–25 pA) in response to picrotoxin. In addition to being a noncompetitive antagonist at GABAARs, picrotoxin also blocks homomeric glycine receptors (GlyRs). Application of the GlyR antagonist strychnine caused a modest but consistent shift (∼15 pA) in membrane current, without affecting spontaneous synaptic events, consistent with the tonic activation of GlyRs. Further investigation showed that these neurons respond in a concentration-dependent manner to glycine and taurine. Inhibition of glycine transporter 1 (GlyT1) with sarcosine resulted in an inward current and an increase of the strychnine-sensitive current. Our data demonstrate the existence of functional GlyRs in layer II/III of the mPFC and a role for these receptors in tonic inhibition that can have an important influence on mPFC excitability and signal processing.

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