Dextrorphan Reduces Infarct Volume, Vascular Injury, and Brain Edema after Ischemic Brain Injury

1996 ◽  
Vol 13 (4) ◽  
pp. 215-222 ◽  
Author(s):  
CHENG DU ◽  
RONG HU ◽  
CHUNG Y. HSU ◽  
DENNIS W. CHOI
Keyword(s):  
Brain Injury ◽  
Brain Edema ◽  
Vascular Injury ◽  
Infarct Volume ◽  
Ischemic Brain Injury ◽  
Ischemic Brain

EDA-Containing Fibronectin Aggravates Ischemic Brain Injury In Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 330-330
Author(s):  
Anil Chauhan ◽  
Mohammad M Khan ◽  
Chintan Gandhi ◽  
Neelam Chauhan ◽  
Asgar Zaheer ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Experimental Model ◽  
Vascular Injury ◽  
Laser Doppler Flowmetry ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Ischemic Brain Injury ◽  
Doppler Flowmetry ◽  
Ischemic Brain

Abstract Abstract 330 Background: Fibronectin (FN) is a dimeric glycoprotein that plays an important role in several cellular processes, such as embryogenesis, malignancy, hemostasis, wound healing and maintenance of tissue integrity. FN is a ligand for many members of the integrin family (e.g. αIIbβ3, α5β1, α4β1, α9β1, αvβ3 and αvβ5) and also binds to thrombosis-related proteins including heparin, collagen and fibrin. FN generates protein diversity as a consequence of alternative processing of a single primary transcript. Two forms of FN exist; soluble plasma FN (pFN), which lacks the alternatively-spliced Extra Domain A (EDA); and insoluble cellular FN (cFN), which contains EDA. FN containing EDA (EDA+FN) is normally absent in plasma of human and mouse but EDA+FN has been found in patients with vascular injury secondary to vasculitis, sepsis, acute major trauma or ischemic stroke. We tested the hypothesis that elevated levels of plasma EDA+FN increase brain injury in an experimental model of ischemic stroke in mice. Model and Method: We used two genetically modified mouse strains: EDA+/+ mice contain optimized spliced sites at both splicing junctions of the EDA exon and constitutively express only EDA+FN, whereas EDA-/- mice contain an EDA-null allele of the EDA exon and express only FN lacking EDA. Control EDAwt/wt mice contain the wild-type FN allele. Transient focal cerebral ischemia was induced by 60 minutes of occlusion of the right middle cerebral artery with a 7.0 siliconized filament in male mice (8-10 weeks in age). Mice were anesthetized with 1–1.5% isoflurane mixed with medical air. Body temperature was maintained at 37°C ± 1.0 using a heating pad. Laser Doppler flowmetry was used to confirm induction of ischemia and reperfusion. At 23 hours after MCAO, mice were evaluated for neurological deficits as a functional outcome and were sacrificed for quantification of infarct volume. For morphometric measurement eight 1 mm coronal sections were stained with 2% triphenyl-2, 3, 4-tetrazolium-chloride (TTC). Sections were digitalized and infarct areas were measured blindly using NIS elements. Result: In EDA+/+ mice the percentage of infarct volume (mean ± SEM: 37.25 ± 4.11, n= 12,) in the ipsilateral (ischemic) hemisphere was increased by approximately two-fold compared to EDA wt/wt mice (mean ± SEM: 22.33 ± 3.39, n=11; P< 0.05, ANOVA) or EDA-/- mice (mean ± SEM: 21.72 ± 2.94, n=9). Regional cerebral blood flow during ischemia was not different among groups as assessed by laser Doppler flowmetry. The percentage increase in infarct volume in the EDA+/+ mice correlated well with severe neurological deficits (motor-deficit assessed by a four-point neurological score scale) compared to EDA wt/wt or EDA-/- mice. Because both thrombosis and inflammation contributes to brain injury during ischemic stroke, we investigated the time to form an occlusive thrombus in ferric-chloride carotid artery injury model by intravital microscopy. EDA+/+ mice demonstrated significantly faster time to occlusion (mean ± SEM: 12.35 ± 1.51 n=12,) compared to EDAwt/wt (Mean ± SEM: 17.27 ± 1.72 min, n=13, P<0.05, ANOVA) or EDA-/- (Mean ± SEM: 15.61 ± 1.76, n=11) mice. Additionally, the inflammatory response in the ischemic region was increased by two fold in EDA+/+ mice compared to EDA wt/wt and EDA-/- mice as sensed by myeloperoxidase activity and immunohistochemical analysis of neutrophils. Conclusion: EDA-containing FN is pro-thrombotic and pro-inflammatory, and aggravates ischemic brain injury in an experimental model of stroke in mice. The presence of EDA+FN in plasma may be a risk factor for vascular injury secondary to ischemic stroke. Disclosures: No relevant conflicts of interest to declare.

Abstract TMP69: Endoglin Deficiency Exacerbates Ischemic Brain Injury

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Fanxia Shen ◽  
Vincent Degos ◽  
Zhenying Han ◽  
Eun-Jung Choi ◽  
William L. Young ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Paradoxical Embolism ◽  
Artery Occlusion ◽  
Vascular Density ◽  
Ischemic Brain Injury ◽  
Myocardial Repair ◽  
Ischemic Brain ◽  
Removal Time ◽  
Adhesive Removal

Background and Objective: Endoglin (Eng) deficiency causes hereditary hemorrhagic telangiectasia (HHT) and impairs myocardial repair. Pulmonary arteriovenous malformations in HHT patients are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that Eng deficiency exacerbates ischemic brain injury. Methods: Eng heterozygous ( Eng +/- ) mice and wild type (WT) mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Infarct volume and CD68 + cells were quantified 3 days and vascular density was determined 60 days after pMCAO. Behavior was assessed by corner test and adhesive removal test at 3, 15, 30 and 60 days after pMCAO. Matrix metalloproteinase 9 (Mmp9) and Notch1 expression in bone marrow (BM)-derived macrophages from Eng +/- and WT were analyzed using real-time RT-PCR. Results: Eng +/- mice had a larger Infarct volume than WT mice (22±6% of the affected hemisphere vs. 16±6%, p=0.04). Eng +/- mice had longer adhesive-removal time (p<0.05) and more frequent turning to the lesion side than WT mice at 15, 30 and 60 days (p<0.05) after pMCAO. Both groups had similar numbers of CD68 + cells in the peri-infarct area at 3 days after pMCAO (370±80 vs 338±44 cells/mm 2 , p=0.37), but Eng +/- mice had lower peri-infarct vessel density (417±69 vs 490±52 vessels/mm 2 , p=0.05) at 60 days after pMCAO. Up-regulation of Mmp9 and Notch1 expression in response to VEGF was attenuated in Eng +/- BM-derived macrophages. Conclusions: Endoglin deficiency exacerbated brain injury and behavior dysfunction in mice after pMCAO and was associated with reduced angiogenesis. Although macrophage homing was not affected, reduced expression of two angiogenic-related genes, Mmp9 and Notch1 , by Eng +/- BM-derived macrophages suggests a potential role of these cells in recovery from an ischemic injury.

Abstract T P210: Splenectomy Attenuates Sex Differences in Infarct Volume Following Experimental Stroke in Mice

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Jianming Wang ◽  
Sheetal Bodhankar ◽  
Halina Offner ◽  
Stephanie J Murphy
Keyword(s):  
Sex Differences ◽  
Blood Glucose ◽  
Brain Injury ◽  
Infarct Volume ◽  
Blood Gases ◽  
Experimental Stroke ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Male And Female ◽  
Female Mice

It is now increasingly clear that human stroke can have other serious consequences besides brain damage that can impact on patient survival and recovery. For example, many stroke patients succumb to CNS injury-induced immunodepression and fatal infections. Our prior work suggests that evolving cerebral ischemic injury elicits a cycle of injury from brain-to-spleen-to-brain that is strongly influenced by sex. We determined if splenic immunocytes are important in contributing to sex differences in post-ischemic brain injury. Male and female C57BL/6J mice were splenectomized 14 days before experimental stroke. Male and female mice with or without splenectomy (n=9-10 per group) then underwent 60 min of middle cerebral artery occlusion (MCAO) via intraluminal filament. Laser-Doppler flowmetry (LDF) was used to monitor cortical perfusion. All mice were euthanized and brains collected at 96 hours of reperfusion. Infarct volume (% corrected contralateral structure) was determined by image analysis of coronal brain slices stained with 2,3,5-triphenyltetrazolium chloride. Mean arterial blood pressure (MABP), blood gases (pH, P a O 2 , P a CO 2 ), and blood glucose were measured at 30 min MCAO and at 15 min of reperfusion in separate groups of male and female mice with or without splenectomy (n=5 per group). Relative LDF changes (% baseline), MABP, blood gases, and blood glucose during and after MCAO were comparable among the experimental groups. We observed that infarct volume in females (cortex, 41±4%; striatum, 55±6%) was smaller ( P <0.05) compared to males (cortex, 52±3%; striatum, 75±3%) at 96 hours of reperfusion. However, no differences (cortex, P =0.313; striatum, P =0.601) in infarct volume were seen between splenectomized male (cortex, 43±4%; striatum, 51±7%) and female (cortex, 38±4%; striatum, 46±5%) mice. Our data suggest that removal of all splenocyte lineages via splenectomy attenuates sex differences in post-ischemic brain injury. Future studies will evaluate the role of different splenic immunocyte subsets, such as T or B lymphocytes, on male vs. female ischemic brain outcomes. This study was supported by National Institutes of Health grant NS076013.

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 The Acute-Phase Protein PTX3 is an Essential Mediator of Glial Scar Formation and Resolution of Brain Edema after Ischemic Injury

2013 ◽  
Vol 34 (3) ◽  
pp. 480-488 ◽  
Author(s):  
Beatriz Rodriguez-Grande ◽  
Matimba Swana ◽  
Loan Nguyen ◽  
Pavlos Englezou ◽  
Samaneh Maysami ◽  
...  
Keyword(s):  
Brain Injury ◽  
Brain Edema ◽  
Acute Phase ◽  
Acute Phase Protein ◽  
Ischemic Injury ◽  
Glial Scar ◽  
Scar Formation ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Phase Protein

Acute-phase proteins (APPs) are key effectors of the immune response and are routinely used as biomarkers in cerebrovascular diseases, but their role during brain inflammation remains largely unknown. Elevated circulating levels of the acute-phase protein pentraxin-3 (PTX3) are associated with worse outcome in stroke patients. Here we show that PTX3 is expressed in neurons and glia in response to cerebral ischemia, and that the proinflammatory cytokine interleukin-1 (IL-1) is a key driver of PTX3 expression in the brain after experimental stroke. Gene deletion of PTX3 had no significant effects on acute ischemic brain injury. In contrast, the absence of PTX3 strongly compromised blood–brain barrier integrity and resolution of brain edema during recovery after ischemic injury. Compromised resolution of brain edema in PTX3-deficient mice was associated with impaired glial scar formation and alterations in scar-associated extracellular matrix production. Our results suggest that PTX3 expression induced by proinflammatory signals after ischemic brain injury is a critical effector of edema resolution and glial scar formation. This highlights the potential role for inflammatory molecules in brain recovery after injury and identifies APPs, in particular PTX3, as important targets in ischemic stroke and possibly other brain inflammatory disorders.

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.

Targeting brain-spleen crosstalk after stroke: new insights into stroke pathology and treatment

2021 ◽  
Vol 19 ◽  
Author(s):  
Dong Han ◽  
Hang Liu ◽  
Yan Gao ◽  
Juan Feng
Keyword(s):  
Brain Injury ◽  
Cytokine Production ◽  
Infarct Volume ◽  
Secondary Brain Injury ◽  
Ischemic Brain Injury ◽  
Spleen Cells ◽  
Ischemic Brain ◽  
Stroke Treatment ◽  
Drug Studies ◽  
Clinical Drug

: The immune response following acute stroke has received great attention. The spleen is an important immune organ, and more and more studies have shown that brain-spleen crosstalk after stroke plays an important role in its development and prognosis. There are many mechanisms of spleen activation after stroke, including activation of the sympathetic nervous system, the production of chemokines, and antigen presentation in the damaged brain. The changes in the spleen after stroke are mainly reflected in morphology, changes to immune cells, and cytokine production. Once activated, the spleen contracts, undergoes cellular changes, and releases inflammatory cytokines. Some studies have also shown that spleen cells specifically migrate to the site of primary brain injury. The size of spleen is also negatively correlated with infarct volume — the more serious the spleen atrophy, the larger the infarct volume. Therefore, a comprehensive understanding of the dynamic response of the spleen to stroke will not only enable understanding of the evolution of ischemic brain injury but will also enable identification of potential targets for stroke treatment. Here, we review recent basic and clinical drug studies on the spleen as a target for the treatment of stroke, focusing on therapeutic strategies for regulating the splenic response and inhibiting secondary brain injury.

scholarly journals Attenuation of Reactive Gliosis Does Not Affect Infarct Volume in Neonatal Hypoxic-Ischemic Brain Injury in Mice

PLoS ONE ◽  
2010 ◽  
Vol 5 (4) ◽  
pp. e10397 ◽  
Author(s):  
Katarina Järlestedt ◽  
Catherine I. Rousset ◽  
Maryam Faiz ◽  
Ulrika Wilhelmsson ◽  
Anders Ståhlberg ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Reactive Gliosis ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Hypoxic Ischemic Brain Injury

scholarly journals Endothelin-1-mediated cerebrovascular remodeling is not associated with increased ischemic brain injury in diabetesThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (8) ◽  
pp. 788-795 ◽  
Author(s):  
Weiguo Li ◽  
Aisha I. Kelly-Cobbs ◽  
Erin M. Mezzetti ◽  
Susan C. Fagan ◽  
Adviye Ergul
Keyword(s):  
Brain Injury ◽  
Cerebral Perfusion ◽  
Infarct Volume ◽  
Cerebral Arteries ◽  
Age Groups ◽  
Diabetic Rats ◽  
Ischemic Brain Injury ◽  
Dependent Manner ◽  
Ischemic Brain ◽  
Neurovascular Damage

Diabetes increases the risk of as well as poor outcome after stroke. Matrix metalloprotease (MMP) activation disrupts blood–brain barrier integrity after cerebral ischemia. We have previously shown that type 2 diabetes promotes remodeling of middle cerebral arteries (MCA) characterized by increased media/lumen (M/L) ratio and MMP activity in an endothelin (ET)-1-dependent manner in the Goto–Kakizaki (GK) rat model. In the present study, we examined the effects of ET-1-mediated vascular remodeling on neurovascular damage following cerebral ischemic injury in GK rats 5 and 12 weeks after the onset of diabetes. The MCA structure, cerebral perfusion as well as infarct size, and hemorrhage were measured in control and diabetic rats subjected to transient MCA occlusion. M/L ratio was increased after 12 but not 5 weeks of diabetes. The baseline cerebral perfusion was lower and the infarct volume smaller in diabetic rats in both age groups. The incidence of hemorrhagic transformation was higher after 5 weeks of diabetes as compared to that after 12 weeks or in the control groups. These findings provide evidence that ET-1-mediated cerebrovascular remodeling does not worsen the neurovascular damage of ischemic brain injury in diabetes. It is possible that this early remodeling response is compensatory in nature to regulate vascular tone and integrity, especially when ischemia is layered on diabetic vascular disease.

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