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 Endocannabinoid response in acute ischemic stroke: elevated 2-arachidonoylglycerol

2020 ◽  
Author(s):  
Marina Buciuc ◽  
Gian Marco Conte ◽  
Eugene L. Scharf
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Symptom Onset ◽  
Therapeutic Potential ◽  
Infarct Volume ◽  
Closed Head Injury ◽  
Acute Cerebral Ischemia ◽  
Ischemic Attack

ABSTRACTBackground and purposeEndocannabinoids are hypothesized to have anti-inflammatory and neuroprotective properties and hold therapeutic potential in the acute phase response mechanisms during acute cerebral ischemia and closed head injury. We set to describe the plasma levels of endocannabinoids and related ethanolamides during acute and subacute phases of cerebral ischemia.MethodsWe conducted a prospective observational study of plasma endocannabinoid levels in patients with acute ischemic stroke or transient ischemic attack. Two blood samples were collected: T1 (<12 hours from symptom onset) and T2 (>24 hours from symptom onset). N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were quantified by liquid chromatography mass spectrometry.ResultsTwenty-three patients met inclusion criteria. Median (interquartile range): Age – 76 years (60-81); body mass index - 25.6 (23.6-30.4); National Institutes of Health Stroke Scale score-5(3-13); infarct volume - 1.4 cm3 (0.5-8.6). Higher 2-AG levels at T1 were correlated with smaller infarct volumes (Spearman ƿ=-0.48, p=0.0206). Levels of 2-AG were elevated at T2 compared to T1 in 48% of patients (median difference - 310.3nM, 95% CI 194.1-497.3; p=0.001); AEA, PEA and OEA did not differ between T1 and T2, p>0.05. Patients with elevated 2-AG at T2 had larger infarct volumes, p=0.0178, lower frequency of embolectomy performed, p=0.0373, but no difference in neurological disability 90 days after the ischemic event compared to patients without 2-AG elevation.Conclusion2-AG increases significantly in early phases of ischemic stroke. The final mechanistic role of 2-AG in acute ischemic stroke is to be determined in further studies.

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).

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 Update on therapies for acute ischemic stroke

2000 ◽  
Vol 8 (5) ◽  
pp. 1-5 ◽  
Author(s):  
Dean D. Kindler ◽  
George A. Lopez ◽  
Bradford B. Worrall ◽  
Karen C. Johnston
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Emerging Therapies ◽  
Type Plasminogen Activator ◽  
Acute Cerebral Ischemia ◽  
Promising Treatment

Acute ischemic stroke is now considered a neurological emergency for which there are new therapies. Neurosurgeons and neurologists need to remain apprised of advances in this field. The authors discuss approved and emerging therapies for patients suffering from acute ischemic stroke, based on a review of recent publications. Currently, intravenous tissue-type plasminogen activator is the only Food and Drug Administration–approved therapy for acute ischemic stroke. Intraarterial delivery of thrombolytics is a promising treatment and may be effective in selected patients. Other therapies for acute cerebral ischemia are intriguing but still in the investigational stages.

Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury

1989 ◽  
Vol 256 (2) ◽  
pp. H589-H593 ◽  
Author(s):  
T. H. Liu ◽  
J. S. Beckman ◽  
B. A. Freeman ◽  
E. L. Hogan ◽  
C. Y. Hsu
Keyword(s):  
Hydrogen Peroxide ◽  
Superoxide Dismutase ◽  
Polyethylene Glycol ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Free Radical Scavengers ◽  
Ischemic Brain Injury ◽  
Ischemic Brain

Superoxide dismutase and catalase enzymatically scavenge superoxide and hydrogen peroxide, respectively. Conjugation of polyethylene glycol to superoxide dismutase (PEG-SOD) or catalase (PEG-CAT) prolongs the circulatory half-life of the native enzymes and enhances their intracellular access. We studied the protective effect of these free radical scavengers on ischemic brain injury using a rat model of focal cerebral ischemia, which is suitable for therapeutic trials. Intravenous administration of PEG-SOD (10,000 U/kg) and PEG-CAT (10,000 U/kg) before ischemia reduced the infarct volume (treatment, 139 +/- 9 mm3, means +/- SE, N = 38; placebo, 182 +/- 8 mm3, n = 37, P less than 0.002). This finding supports the concept that superoxide and hydrogen peroxide contribute to brain injury following focal cerebral ischemia.

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 T MP53: Whole Blood Immuno-Chromatography for Rapid Detection of Cerebral Ischemia in the Pre-Hospital Setting

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Luther C Pettigrew ◽  
Melissa A Bradley-Whitman ◽  
Mark A Lovell
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Whole Blood ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Hospital Setting ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Ischemic Reperfusion ◽  
Arterial Blood

BACKGROUND: Pre-hospital detection of ischemic brain injury will exclude stroke mimics and refine patient triage. Using “dipstick” immuno-chromatography, we validated a rapid-sequence method to identify visinin-like protein-1 (VILIP-1), a neuronal injury marker, in blood sampled after focal cerebral ischemia in rats. METHODS: Transgenic (Tg) rats were constructed to over-express tumor necrosis factor-alpha (TNFα) in brain. Suture-occlusion of the middle cerebral artery (MCAO) was performed in TNFα-Tg animals and wild type (WT) littermates for 1 hr. Arterial blood was sampled at pre-ischemic baseline, after 60 min of MCAO, and at 15 min or 24 hrs of post-ischemic reperfusion. VILIP-1 immuno-reactivity was normalized to pre-ischemic baseline and compared to sham-ischemic animals. Brain infarct volume was measured at 24 hrs. VILIP-1 immuno-reactivity was then correlated with infarct volume to derive Pearson product moment. RESULTS: VILIP-1 immuno-reactivity was increased after 24 hrs of post-ischemic reperfusion in TNFα-Tg animals (133 ± 13 [SD]% of baseline) compared to sham-ischemic rats (100 ± 22; p ≤ 0.05; ANOVA; n = 5 per group). At 15 min (159 ± 36%) and 24 hrs (above), VILIP-1 expression was greater than pre-ischemic baseline ( p ≤ 0.05). Immuno-reactivity of VILIP-1 at 15-min post-ischemic reperfusion was strongly correlated with infarct volume measured at 24 hrs in TNFα-Tg rats (Pearson 0.79; p ≤ 0.01). CONCLUSIONS: Whole blood immuno-chromatography of VILIP-1 is feasible and correlates positively with infarct volume measured at 24 hrs in the rat. These promising results underscore the need to study VILIP-1 immuno-reactivity as an indicator of ischemic brain injury in the pre-hospital setting.

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.

scholarly journals Mito-Tempo prevents nicotine-induced exacerbation of ischemic brain damage

2018 ◽  
Vol 125 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Chun Li ◽  
Hong Sun ◽  
Guodong Xu ◽  
Kimberly D. McCarter ◽  
Jiyu Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Damage ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutrophil Infiltration ◽  
Neurological Deficits ◽  
Sprague Dawley ◽  
Ischemic Brain Damage ◽  
Mitochondrial Oxidative Stress ◽  
Ischemic Brain

Nicotine may contribute to the pathogenesis of cerebrovascular disease via the generation of reactive oxygen species (ROS). Overproduction of ROS leads to brain damage by intensifying postischemic inflammation. Our goal was to determine the effect of Mito-Tempo, a mitochondria-targeted antioxidant, on ischemic brain damage and postischemic inflammation during chronic exposure to nicotine. Male Sprague-Dawley rats were divided into four groups: control, nicotine, Mito-Tempo-treated control, and Mito-Tempo-treated nicotine. Nicotine (2 mg·kg−1·day−1) was administered via an osmotic minipump for 4 wk. Mito-Tempo (0.7 mg·kg−1·day−1ip) was given for 7 days before cerebral ischemia. Transient focal cerebral ischemia was induced by occlusion of the middle cerebral artery for 2 h. Brain damage and inflammation were evaluated after 24 h of reperfusion by measuring infarct volume, expression of adhesion molecules, activity of matrix metalloproteinase, brain edema, microglial activation, and neutrophil infiltration. Nicotine exacerbated infarct volume and worsened neurological deficits. Nicotine did not alter baseline ICAM-1 expression, matrix metallopeptidase-2 activity, microglia activation, or neutrophil infiltration but increased these parameters after cerebral ischemia. Mito-Tempo did not have an effect in control rats but prevented the chronic nicotine-induced augmentation of ischemic brain damage and postischemic inflammation. We suggest that nicotine increases brain damage following cerebral ischemia via an increase in mitochondrial oxidative stress, which, in turn, contributes to postischemic inflammation.NEW & NOTEWORTHY Our findings have important implications for the understanding of mechanisms contributing to increased susceptibility of the brain to damage in smokers and users of nicotine-containing tobacco products.

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