Inflammation After Stroke: Mechanisms and Therapeutic Approaches

Ahmad, Muzamil; Graham, Steven H.

doi:10.1007/s12975-010-0023-7

Cited by 84 publications

(62 citation statements)

References 175 publications

(178 reference statements)

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“…Furthermore, using a cell culture model of human BBB established with relatively late passage endothelial cells and astrocytes, in this study only one factor, i.e., glucose, out of many involved in ischemic damage could be manipulated, whereas a number of pro-inflammatory cytokines and circulating components during an ischemic stroke, notably tumor necrosis factor-a, interleukin-6, vascular endothelial growth factor, and thrombin, are known to affect BBB permeability. 37,38 …”

Section: Discussionmentioning

confidence: 99%

PKC-βExacerbatesin vitroBrain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

Srivastava

Shao

Bayraktutan

2013

J Cereb Blood Flow Metab

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Stroke patients with hyperglycemia (HG) develop higher volumes of brain edema emerging from disruption of blood-brain barrier (BBB). This study explored whether inductions of protein kinase C-b (PKC-b) and RhoA/Rho-kinase/myosin-regulatory light chain-2 (MLC2) pathway may account for HG-induced barrier damage using an in vitro model of human BBB comprising human brain microvascular endothelial cells (HBMEC) and astrocytes. Hyperglycemia (25 mmol/L D-glucose) markedly increased RhoA/Rho-kinase protein expressions (in-cell westerns), MLC2 phosphorylation (immunoblotting), and PKC-b (PepTag assay) and RhoA (Rhotekinbinding assay) activities in HBMEC while concurrently reducing the expression of tight junction protein occludin. Hyperglycemiaevoked in vitro barrier dysfunction, confirmed by decreases in transendothelial electrical resistance and concomitant increases in paracellular flux of Evan's blue-labeled albumin, was accompanied by malformations of actin cytoskeleton and tight junctions. Suppression of RhoA and Rho-kinase activities by anti-RhoA immunoglobulin G (IgG) electroporation and Y-27632, respectively prevented morphologic changes and restored plasma membrane localization of occludin. Normalization of glucose levels and silencing PKC-b activity neutralized the effects of HG on occludin and RhoA/Rho-kinase/MLC2 expression, localization, and activity and consequently improved in vitro barrier integrity and function. These results suggest that HG-induced exacerbation of the BBB breakdown after an ischemic stroke is mediated in large part by activation of PKC-b.

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Section: Discussionmentioning

confidence: 99%

PKC-βExacerbatesin vitroBrain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

Srivastava

Shao

Bayraktutan

2013

J Cereb Blood Flow Metab

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“…Inflammation takes part in the recovery after stroke and cerebral injury, but, simultaneously it is one of the threats which may worsen the stroke condition [35]. Inflammation during stroke is intermediated by both soluble factors, especially cytokines and also cellular components such as leukocytes and microglia, many of which have pro-inflammatory properties with promoting or destructive consequences [3,89]. ROS are generated as part of the natural immune response by inflammatory cells.…”

Section: Oxidative Stress-mediated Catastrophes Inflammationmentioning

confidence: 99%

Oxidative stress – assassin behind the ischemic stroke

Hanumanthappa

Joseph²,

Shashikumar³

et al. 2012

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“…Therefore, a significant hiatus exists during which no means of effective medical management is available for patients with AIS. Moreover, despite numerous clinical trials conducted to salvage cells from death, no significant breakthrough has been made to improve the outcome of stroke patients (5,6).…”

mentioning

confidence: 99%

“…Such cells, as infiltrate within the peri-infarcted areas of brain tissues from AIS patients (9, 10), become intimately involved in all stages of the ischemic cascade (7,8). Studies in experimental stroke have indicated that all these cells contribute to the death of ischemic neurons by promoting focal inflammatory reactions, direct killing, triggering of antigen-specific immune responses, or alterations in neuronal excitability (6,(10)(11)(12).…”

mentioning

confidence: 99%

Impact of an immune modulator fingolimod on acute ischemic stroke

Zhang

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

237

200

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Peripheral lymphocytes entering brain ischemic regions orchestrate inflammatory responses, catalyze tissue death, and worsen clinical outcomes of acute ischemic stroke (AIS) in preclinical studies. However, it is not known whether modulating brain inflammation can impact the outcome of patients with AIS. In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited 22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone (controls) or standard management plus fingolimod (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days. Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs. −1, respectively (P = 0.0001). Neurological rehabilitation was faster in the fingolimod-treated group. Enlargement of lesion size was more restrained between baseline and day 7 than in controls (9 vs. 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events occurred. We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 h of disease onset was safe, limited secondary tissue injury from baseline to 7 d, decreased microvascular permeability, attenuated neurological deficits, and promoted recovery.acute ischemic stroke | immune modulation | fingolimod

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Inflammation After Stroke: Mechanisms and Therapeutic Approaches

Cited by 84 publications

References 175 publications

PKC-βExacerbatesin vitroBrain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

PKC-βExacerbatesin vitroBrain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

Oxidative stress – assassin behind the ischemic stroke

Impact of an immune modulator fingolimod on acute ischemic stroke

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