scholarly journals Human-Albumin Neuroprotection in Acute Ischemic Stroke: Marked Efficacy at Moderate Doses, with a Broad Therapeutic Window.

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 326-326
Author(s):  
Myron D Ginsberg ◽  
Ludmila Belayev ◽  
Yitao Liu ◽  
Weizhao Zhao ◽  
Raul Busto
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Human Albumin ◽  
Global Cerebral Ischemia ◽  
Therapeutic Window ◽  
High Dose ◽  
Neurological Score

58 We have previously shown that high-dose human albumin (Alb) is markedly neuroprotective in focal and global cerebral ischemia and in traumatic brain injury. In this study, we examined the efficacy of moderate, clinically achievable Alb doses and defined the therapeutic window in focal cerebral ischemia. Sprague Dawley rats (n=62) were anesthetized with halothane/nitrous oxide and received 2-h middle cerebral artery occlusion (MCAo) by intraluminal suture. Neurological status was evaluated during occlusion (60 min) and daily for 3 days after MCAo. In the dose-response study, animals were given either 25% Alb in doses 0.63 or 1.25 g/kg , or 0.9% saline vehicle, i.v. immediately after suture removal (n=5 each). In the therapeutic window study, 1.25 g/kg Alb was administered at either 2 h, 3 h, 4 h, or 5 h after onset of stroke (i.e., 0 to 3 h after onset of reperfusion) (n=9–10 ea.). Three days after MCAo, brains were perfusion-fixed, and image-processing was used to compute infarct volumes and brain swelling. Both moderate Alb doses (0.63 and 1.25 g/kg) significantly improved the neurological score compared to vehicle rats at 24h, 48h and 72h; and markedly reduced cortical infarct volume (by 66±14% and 95±4%, respectively), striatal infarct volume (by 54±8% and 52±14%), and total infarct volume (by 58±5% and 67±9%, respectively). Brain edema was virtually eliminated by Alb treatment. In the therapeutic window study, even when treatment was initiated as late as 4 hours after onset of MCAo, 1.25 g/kg Alb led to significantly improved neurological score and highly significant reductions of infarct areas in cortex (68% reduction), subcortical regions (52% reduction), and total infarct (61% reduction). The striking efficacy and broad therapeutic window of moderate-dose Alb therapy in experimental focal ischemia strongly supports the feasibility of initiating early-phase clinical trials of this promising agent in patients with acute ischemic stroke. This work was supported by NIH Grant NS05820 (MDG) and by AHA Initial Investigator Award (LB).

scholarly journals Mucosal‐Associated Invariant T Cells Are Involved in Acute Ischemic Stroke by Regulating Neuroinflammation

2021 ◽  
Author(s):  
Sho Nakajima ◽  
Ryota Tanaka ◽  
Kazuo Yamashiro ◽  
Asako Chiba ◽  
Daisuke Noto ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Flow Cytometric Analysis ◽  
Interleukin 17 ◽  
Ischemic Brain ◽  
Mait Cells ◽  
Acute Cerebral Ischemia

Background Mucosal‐associated invariant T (MAIT) cells have been associated with inflammation in several autoimmune diseases. However, their relation to ischemic stroke remains unclear. This study attempted to elucidate the role of MAIT cells in acute ischemic stroke in mice. Methods and Results We used MR1 knockout C57BL/6 (MR1 −/− ) mice and wild‐type littermates (MR1 +/+ ). After performing a transient middle cerebral artery occlusion (tMCAO), we evaluated the association with inflammation and prognosis in the acute cerebral ischemia. Furthermore, we analyzed the tMCAO C57BL/6 mice administered with the suppressive MR1 ligand and the vehicle control. We also evaluated the infiltration of MAIT cells into the ischemic brain by flow cytometry. Results showed a reduction of infarct volume and an improvement of neurological impairment in MR1 −/− mice (n=8). There was a reduction in the number of infiltrating microglia/macrophages (n=3–5) and in their activation (n=5) in the peri‐infarct area of MR1 −/− mice. The cytokine levels of interleukin‐6 and interleukin‐17 at 24 hours after tMCAO (n=3–5), and for interleukin‐17 at 72 hours after tMCAO (n=5), were lower in the MR1 −/− mice. The administration of the suppressive MR1 ligand reduced the infarct volume and improved functional impairment (n=5). Flow cytometric analysis demonstrated there was a reduction of MAIT cells infiltrating into the ischemic brain at 24 hours after tMCAO (n=17). Conclusions Our results showed that MAIT cells play an important role in neuroinflammation after focal cerebral ischemia and the use of MAIT cell regulation has a potential role as a novel neuroprotectant for the treatment of acute ischemic stroke.

scholarly journals Hypothermic neuroprotection against acute ischemic stroke: The 2019 update

2019 ◽  
Vol 40 (3) ◽  
pp. 461-481 ◽  
Author(s):  
Longfei Wu ◽  
Di Wu ◽  
Tuo Yang ◽  
Jin Xu ◽  
Jian Chen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Brain Injuries ◽  
Focal Cerebral Ischemia ◽  
Global Cerebral Ischemia ◽  
Neuroprotective Effects ◽  
Neuroprotective Strategies ◽  
Selective Cooling ◽  
Ischemic Encephalopathy

Acute ischemic stroke is a leading cause of death and disability worldwide. Therapeutic hypothermia has long been considered as one of the most robust neuroprotective strategies. Although the neuroprotective effects of hypothermia have only been confirmed in patients with global cerebral ischemia after cardiac arrest and in neonatal hypoxic ischemic encephalopathy, establishing standardized protocols and strictly controlling the key parameters may extend its application in other brain injuries, such as acute ischemic stroke. In this review, we discuss the potential neuroprotective effects of hypothermia, its drawbacks evidenced in previous studies, and its potential clinical application for acute ischemic stroke especially in the era of reperfusion. Based on the different conditions between bench and bedside settings, we demonstrate the importance of vascular recanalization for neuroprotection of hypothermia by analyzing numerous literatures regarding hypothermia in focal cerebral ischemia. Then, we make a thorough analysis of key parameters of hypothermia and introduce novel hypothermic therapies. We advocate in favor of the process of clinical translation of intra-arterial selective cooling infusion in the era of reperfusion and provide insights into the prospects of hypothermia in acute ischemic stroke.

scholarly journals Catheter based selective hypothermia reduces stroke volume during focal cerebral ischemia in swine

2015 ◽  
Vol 8 (4) ◽  
pp. 418-422 ◽  
Author(s):  
Thomas K Mattingly ◽  
Lynn M Denning ◽  
Karen L Siroen ◽  
Barb Lehrbass ◽  
Pablo Lopez-Ojeda ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Stroke Volume ◽  
Acute Ischemic Stroke ◽  
Brain Mri ◽  
Global Cerebral Ischemia ◽  
Moderate Hypothermia ◽  
Stroke Model ◽  
Stroke Treatment ◽  
Endovascular Cooling

BackgroundTotal body hypothermia is an established neuroprotectant in global cerebral ischemia. The role of hypothermia in acute ischemic stroke remains uncertain. Selective application of hypothermia to a region of focal ischemia may provide similar protection with more rapid cooling and elimination of systemic side effects. We studied the effect of selective endovascular cooling in a focal stroke model in adult domestic swine.MethodsAfter craniotomy under general anesthesia, a proximal middle cerebral artery branch was occluded for 3 h, followed by 3 h of reperfusion. In half of the animals, selective hypothermia was induced during reperfusion using a dual lumen balloon occlusion catheter placed in the ipsilateral common carotid artery. Following reperfusion, the animals were sacrificed. Brain MRI and histology were evaluated by experts who were blinded to the intervention.Results25 animals were available for analysis. Using selective hypothermia, hemicranial temperature was successfully cooled to a mean of 26.5°C. Average time from start of perfusion to attainment of moderate hypothermia (<30°C) was 25 min. Mean MRI stroke volumes were significantly reduced by selective cooling (0.050±0.059 control, 0.005±0.011 hypothermia (ratio stroke:hemisphere volume) (p=0.046). Stroke pathology volumes were reduced by 42% compared with controls (p=0.256).ConclusionsSelective moderate hypothermia was rapidly induced using endovascular techniques in a clinically realistic swine stroke model. A significant reduction in stroke volume on MRI was observed. Endovascular selective hypothermia can provide neuroprotection within time frames relevant to acute ischemic stroke treatment.

VWF-Cleaving Protease ADAMTS13 Reduces Brain Injury Following Ischemic Stroke in Mice: Essential Role for VWF in Stroke

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 259-259
Author(s):  
Bing-Qiao Zhao ◽  
Anil kumar Chauhan ◽  
Ian S. Patten ◽  
Michael Dockal ◽  
Friedrich Scheiflinger ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Essential Role ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Recombinant Tissue Plasminogen Activator ◽  
Protective Role ◽  
Artery Occlusion ◽  
Type I ◽  
Deficient Mice

Abstract Ischemic stroke is the second leading cause of death and disability. The only approved therapy available is recombinant tissue plasminogen activator (tPA), but its use remains limited. Therefore, there is a need for an alternative drug. Platelets and their adhesion receptors play a crucial role in modulating infarct size during ischemic stroke. ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) is a plasma metalloprotease that cleaves von Willebrand factor (VWF) an important adhesion molecule for platelets at sites of vascular injury. In patients, an increase in circulating levels of VWF and a decrease in ADAMTS13 activity are considered risk factors for ischemic stroke. By using genetically-modified mice we have previously shown that ADAMTS13 down regulates both thrombosis and inflammation and recombinant human ADAMTS13 down regulates platelet thrombi in injured arterioles. All these processes were dependent on VWF. We therefore hypothesize that ADAMTS13 has a protective role after ischemic stroke. In this study, we show that VWF deficiency or VWF heterozygosity in mice reduces infarct volume by two-fold after focal cerebral ischemia compared to wild-type (WT) in the middle cerebral artery occlusion (MCAO) stroke model. Furthermore, infusion of recombinant human VWF in WT mice not only accelerates thrombosis in the ferric-chloride injured artery model, but also increases infarct volume compared to vehicle-treated controls. These findings suggest an essential role of VWF in modulating infarction after stroke. We also show that ADAMTS13 deficiency in mice results in approximately 20% larger infarcts after cerebral ischemia compared to WT. The larger infarcts observed in ADAMTS13 deficient mice were due to VWF because mice deficient in both ADAMTS13 and VWF had infarct sizes similar to VWF deficient mice. Importantly, infusion of r-human ADAMTS13 immediately before reperfusion (two hour after occlusion) significantly reduced infarct volume (106.2 ± 9.7 mm3 vs 75.8 ± 6.9 mm3, P&lt;0.05). Of note, we observed that ADAMTS13 protein was induced in the ischemic penumbra region of brain after ischemic stroke. Our findings reveal an important role for VWF in modulating infarct volume after ischemic stroke. In addition, recombinant-ADAMTS13 could become a new therapeutic agent for stroke therapy.

scholarly journals Short Therapeutic Window for MK-801 in Transient Focal Cerebral Ischemia in Normotensive Rats

1996 ◽  
Vol 16 (1) ◽  
pp. 107-113 ◽  
Author(s):  
I. Margaill ◽  
S. Parmentier ◽  
J. Callebert ◽  
M. Allix ◽  
R. G. Boulu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptors ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Activity ◽  
Therapeutic Window ◽  
Left Middle Cerebral Artery ◽  
Mk 801 ◽  
Transient Focal Cerebral Ischemia

The present study investigates the role of N-methyl-D-aspartate (NMDA) receptors in a model of transient focal cerebral ischemia in normotensive rats. The left middle cerebral artery and both common carotid arteries were occluded for 60 min. Preliminary studies indicated that this gave reproducible infarctions of the cortex and striatum. These infarctions were the result of severe ischemia followed by complete reperfusion after clamp removal, as showed by striatal tissue Po2 monitoring. Microdialysis indicated that glutamate concentration increased immediately after occlusion and returned to the baseline value 40 min after clamp removal. MK-801 (1 mg kg−1 i.v.), an antagonist of the NMDA glutamatergic receptor, reduced the cortical infarct volume by 29% (p < 0.001) and the striatal infarct volume by 14% (p < 0.05) when given just prior to ischemia, but had no neuroprotective activity when given 30 min after the onset of ischemia. This short therapeutic window for MK-801 suggests that NMDA receptors play only a transient role in reversible focal ischemia in rats.

scholarly journals A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia

2000 ◽  
Vol XXXII (3-4) ◽  
pp. 76-76
Author(s):  
J. Yrjanheikki ◽  
T. Tikka ◽  
R. Keinanen ◽  
G. Goldsteins ◽  
P. H. Chan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Brain Tissue ◽  
Focal Cerebral Ischemia ◽  
The Brain ◽  
Tetracycline Derivative

One of the reasons for the insufficient effectiveness of treatment of acute ischemic stroke may be secondary inflammation of the brain tissue, which, according to the results of modern studies, significantly worsens the consequences and outcome of the disease.

Abstract 2981: Neuroprotective Effect Of Acute Ethanol Administration In Rat With Transient Cerebral Ischemia

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Xiaokun Geng ◽  
Xunming Ji ◽  
Fei Wang ◽  
Yu Wang ◽  
Karam ASMARO ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Elevated Serum ◽  
Transient Cerebral Ischemia ◽  
Alcoholic Beverages ◽  
Ethanol Administration ◽  
Lesion Volume

Background and Purpose _ Despite a focus on the pathological effects of alcohol abuse, numerous studies published over the past several decades also demonstrate beneficial effects of light-to-moderate consumption of alcoholic beverages. Recent studies have demonstrated that elevated serum ethanol levels are associated with increased survival in patients with traumatic brain injury (TBI), suggesting that an acute exposure to alcohol exerts a neuroprotective effect. In a rat model of transient cerebral ischemia, we identified administration of ethanol as a possible treatment for acute ischemic stroke. Methods _Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for two hours. Five sets of experiments were conducted: 1) to determine the dose-response effect of ethanol (0.5, 1.0 and 1.5g/kg) on brain infarction and functional outcome; 2) to determine whether combining ethanol (1.5g/kg) and hypothermia produces synergistic neuroprotection; 3) to determine the therapeutic windows of opportunity for ethanol in stroke; to test whether ethanol promotes intracerebral hemorrhage (ICH) in hemorrhagic or ischemic stroke, or after administration of thrombolytics in ischemic stroke; and 5) to test the affect of ethanol on HIF-1α protein expression. Results —Ethanol at 1.5 g/kg, which produce blood levels (89mg/dL) within the legally intoxicated range for driving (80-100 g/dL), most effectively reduced infarct volume and behavioral dysfunction when administered at 2, 3 or 4 hours after MCAO. We find that ethanol and moderate hypothermia (32-34 °C) exert neuroprotective effects of similar magnitude at both the lesion volume and functional levels, but do not exert a synergistic effect in this model. Ethanol did not promote cerebral hemorrhage in hemorrhagic or ischemic stroke in combination with recombinant tissue plasminogen activator (rt-PA) or urokinase (UK). Up-regulation of HIF-1α protein levels was enhanced by ethanol, in association with reduced brain infarct volume and improved functional recovery in rats subjected to stroke using the same dose (1.5 g/kg). Conclusions —Ethanol exerts a strong neuroprotective effect when administered up to 4 hours after ischemia, and does not promote ICH when used with thrombolytics. Ethanol is a potential neuroprotectant for acute ischemic stroke.

Protein extravasation and cellular uptake after high-dose human-albumin treatment of transient focal cerebral ischemia in rats

1999 ◽  
Vol 827 (1-2) ◽  
pp. 237-242 ◽  
Author(s):  
Michel Remmers ◽  
Rainald Schmidt-Kastner ◽  
Ludmila Belayev ◽  
Baowan Lin ◽  
Raul Busto ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Cellular Uptake ◽  
Focal Cerebral Ischemia ◽  
Human Albumin ◽  
High Dose ◽  
Protein Extravasation ◽  
Transient Focal Cerebral Ischemia

scholarly journals Endonuclease G does not play an obligatory role in poly(ADP-ribose) polymerase-dependent cell death after transient focal cerebral ischemia

2010 ◽  
Vol 299 (1) ◽  
pp. R215-R221 ◽  
Author(s):  
Zhenfeng Xu ◽  
Jian Zhang ◽  
Karen K. David ◽  
Zeng-Jin Yang ◽  
Xiaoling Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Wild Type ◽  
Endonuclease G ◽  
Transient Focal Cerebral Ischemia ◽  
Apoptosis Inducing Factor

Activation of poly(ADP-ribose) polymerase (PARP) and subsequent translocation of apoptosis-inducing factor contribute to caspase-independent neuronal injury from N-methyl-d-aspartate, oxygen-glucose deprivation, and ischemic stroke. Some studies have implicated endonuclease G in the DNA fragmentation associated with caspase-independent cell death. Here, we compared wild-type and endonuclease G null mice to investigate whether endonuclease G plays a role in the PARP-dependent injury that results from transient focal cerebral ischemia. Latex casts did not reveal differences in the cerebral arterial distribution territory or posterior communicating arterial diameter, and the decrease in laser-Doppler flux during middle cerebral artery occlusion was similar in wild-type and endonuclease G null mice. After 90 min of occlusion and 1 day of reperfusion, similar degrees of nuclear translocation of apoptosis-inducing factor and DNA degradation were evident in male wild-type and null mice. At 3 days of reperfusion, infarct volume and neurological deficit scores were not different between male wild-type and endonuclease G null mice or between female wild-type and endonuclease G null mice. These data demonstrate that endonuclease G is not required for the pathogenesis of transient focal ischemia in either male or female mice. Treatment with a PARP inhibitor decreased infarct volume and deficit scores equivalently in male wild-type and endonuclease G null mice, indicating that the injury in endonuclease G null mice remains dependent on PARP. Thus endonuclease G is not obligatory for executing PARP-dependent injury during ischemic stroke.

scholarly journals KLF4 alleviates cerebral vascular injury by ameliorating vascular endothelial inflammation and regulating tight junction protein expression following ischemic stroke

2020 ◽  
Author(s):  
Xinyu Zhang ◽  
Lu Wang ◽  
Zhenxiang Han ◽  
Jing Dong ◽  
Defang Pang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Vascular Injury ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Serum Levels ◽  
Vascular Endothelial ◽  
Endothelial Inflammation ◽  
Cerebral Ischemic ◽  
Cerebral Vascular

Abstract Background Although inflammatory cell adhesion molecules (CAMs) and anti-inflammation factor- kruppel-like transcription factor (KLF) 4 have all been reported to be induced after cerebral ischemic stroke (CIS), the close temporal and spatial relationship between expressions of CAMs and KLF4 following CIS, and whether and how CAMs and KLF-4 contribute to development of CIS-induced vascular injury are still unclear. Methods Here, we first examined the correlation between serum levels of CAMs/KLF4 and infarct volume in acute CIS patients. Then, we determined relationship between CAMs and KLF4 in mice after focal cerebral ischemia. Finally, we investigated the mechanism of KLF4 in protecting against oxygen-glucose deprivation-induced brain endothelial cell injury. Results Our results demonstrated that patients with moderate to severe CIS had higher serum levels of three CAMs including E-selectin, inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) but lower levels of KLF4 at 48 hours after acute event as compared to patients with minor CIS. The expression levels of three CAMs as well as KLF4 all correlated well with the infarct volume in all the CIS subjects at that time. Although the expressions of three CAMs and KLF4 were all induced in the ischemic hemisphere following focal cerebral ischemia, but the peak timing and distribution patterns of their expression were different: the induction of KLF4 lagged behind that of the CAMs in the ischemic penumbra, furthermore, the dual immunofluorescent studies displayed that high expression of KLF4 was always associated with relatively less cerebral vascular endothelial inflammation response in the ischemic hemisphere, and vice versa. Mechanistic analyses revealed that KLF4 alleviated CIS-induced cerebral vascular injury by regulating endothelial expressions of CAMs, nuclear factor-kB and tight junction proteins. Conclusions These data indicate that KLF4 confers vascular protection against cerebral ischemic injury, suggesting that circulating CAMs and KLF4 might be used as potential biomarkers for predicting the prognosis of acute ischemic stroke, and also providing a new proof of concept and potential targets for future prevention and treatment of CIS.

Sign in / Sign up

Export Citation Format

Share Document