scholarly journals Alteplase Treatment does not Increase Brain Injury After Mechanical Middle Cerebral Artery Occlusion in the Rat

2013 ◽  
Vol 33 (11) ◽  
pp. e1-e7 ◽  
Author(s):  
Brad A Sutherland ◽  
Alastair M Buchan
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Infarct Volume ◽  
Recombinant Tissue Plasminogen Activator ◽  
Artery Occlusion ◽  
Carrier Solution ◽  
Tissue Plasminogen ◽  
Cerebral Artery Occlusion

Recanalization of an occluded vessel with recombinant tissue plasminogen activator is an effective strategy for treating acute ischemic stroke. Recombinant tissue plasminogen activator is administered as alteplase, a formulation containing many excipients including L-arginine, the substrate for nitric oxide production. Most studies fail to compare the effects of alteplase on brain injury to its L-arginine carrier solution. This study aimed to verify the previously reported detrimental effects of alteplase after cerebral ischemia and delineate the contribution of L-arginine. Male Wistar rats, subjected to 90 minutes of intraluminal middle cerebral artery occlusion (MCAO), were administered alteplase, the carrier solution or saline upon reperfusion. Neither alteplase nor the carrier affected cerebral blood flow (CBF) restoration throughout the first 60 minutes of reperfusion. Alteplase treatment was associated with increased mortality after MCAO. Twenty-four hours after MCAO, neurologic function and infarct volume did not differ between rats treated with alteplase, the carrier solution, or saline. Irrespective of treatment group, infarct volume was correlated with CBF during reperfusion, neuroscore, and peri-infarct depolarizations. These results suggest that alteplase treatment, independent of thrombolysis, does not cause increased ischemic injury compared with its appropriate carrier solution, supporting the continued use of alteplase in eligible ischemic stroke patients.

THE RELATIONSHIP BETWEEN TIMING OF RECANALIZATION AND CLINICAL OUTCOME OF ISCHEMIC STROKE DUE TO ACUTE MIDDLE CEREBRAL ARTERY OCCLUSION AFTER ULTRASOUND-ENHANCED THROMBOLYSIS

2017 ◽  
pp. 38-43
Author(s):  
Quang Thang Tran ◽  
Dat Anh Nguyen ◽  
Van Chi Nguyen ◽  
Duy Ton Mai ◽  
Van Thinh Le
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Recombinant Tissue Plasminogen Activator ◽  
Artery Occlusion ◽  
Stroke Patients ◽  
Tissue Plasminogen ◽  
Cerebral Artery Occlusion ◽  
The Relationship

Purpose: The relationship between arterial recanalization after use of intravenous recombinant tissue plasminogen activator (rtPA) and outcome is still uncertain. The aim of our study was to evaluate the association between the timing and impact of recanalization on functional outcomes in ischemic stroke patients due to acute middle cerebral artery occlusion. Subjects and methods: Nonrandomized 40 stroke patients with proximal middle arterial occlusion on a prebolus TCD receiving intravenously 0.6 mg/kg rtPA within 4.5 hours after stroke onset were monitored with portable diagnostic TCD equipment and a standard headframe. Complete recanalization was defined as thrombolysis in brain ischemia (TIBI) flow grades 4-5. Results: 40 patients (mean age 67±14 years, NIH Stroke Scale [NIHSS] 16.15±8.6 points) were treated at 180±80 minutes from symptom onset. TCD was monitored continously for 120 minutes. Complete recanalization on TCD within 2 hours after bolus was found in 13 patients (32.5%). In this group, NIHSS decreased quickly at 2 hours and 24 hours. Modified Rankins 0-1point was seen in 92.3% of patients with complete recanalization compared to 37.0% of patients with uncomplete recanalization at 90 days. Non-symptomatic intracranial hemorrhage was seen in 1 patient in the group of complete recanalization. Conclusions: Complete recanalization of middle cerebral arteries within 2 hours after IV rtPA treatment plays a role in predicting the good functional and clinical outcomes after ultrasound-enhanced thrombolysis in acute ischemic stroke patients due to acute middle cerebral artery occlusion. Key words: stroke, recombinant tissue plasminogen activator, transcranial Doppler sonography

Blocking A1 astrocyte conversion with semaglutide attenuates blood-brain barrier disruption in mice after middle cerebral artery occlusion

2021 ◽  
Author(s):  
Qi Zhang ◽  
Chang Liu ◽  
Rubing Shi ◽  
Huimin Shan ◽  
Lidong Deng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Signaling Pathways ◽  
Middle Cerebral Artery Occlusion ◽  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Rna Seq ◽  
Neurobehavioral Outcomes ◽  
Cerebral Artery Occlusion

Abstract Background Astrocytes play an essential role in the modulation of blood-brain barrier function. Neurological diseases induce astrocytes to transform into a neurotoxic A1 phenotype, thus exacerbating brain injury. However, the effect of A1 astrocyte on the function of BBB after stroke is unknown. Method: Adult male ICR mice (n = 78) were subjected to 90-minute transient middle cerebral artery occlusion. Immunohistochemical staining of A1 (C3d) and A2 (S100A10) was performed to characterize phenotypic changes of astrocytes overtime after stroke. Glucagon-like peptide-1 receptor agonist semaglutide was intraperitoneally injected into the mice to inhibit A1 astrocyte. Infarct volume, atrophy volume, neurobehavioral outcomes, and BBB permeability were examined. RNA-seq was adopted to explore the potential targets and signaling pathways of A1 astrocytes induced BBB dysfunction. Results Astrocytes assumed the A2 phenotype at the early stage of ischemic stroke but gradually transformed to the A1 phenotype. Semaglutide treatment reduced M1 microglia polarization and A1 astrocytes conversion after ischemic stroke (p < 0.05). Ischemia induced brain infarct volume, atrophy volume and neuroinflammation were reduced in the semaglutide treated mice. Neurobehavioral outcomes were improved compared to the control mice (p < 0.05). Further study demonstrated that semaglutide treatment reduced the gap formation of tight junction proteins ZO-1, claudin-5 and occludin, as well as IgG leakage following three days of ischemic stroke (p < 0.05). In vitro experiments revealed that A1 astrocyte-conditioned medium disrupted BBB integrity. RNA-seq further showed that A1 astrocytes were enriched in inflammatory factors and chemokines, as well as significantly modulating TNF and chemokine signaling pathways, which are closely related to barrier damage. Conclusion We concluded that astrocytes undergo a conversion from A2 phenotype to A1 phenotype overtime after ischemic stroke. A1 astrocytes aggravated BBB disruption, suggesting that block of A1 astrocytes conversion provides a novel strategy for the treatment of ischemic stroke.

Influence of simultaneous pressor and vasodilatory agents on the evolution of infarct growth in experimental acute middle cerebral artery occlusion

2020 ◽  
pp. neurintsurg-2020-016539
Author(s):  
Niloufar Saadat ◽  
Gregory A Christoforidis ◽  
Yong Ik Jeong ◽  
Mira Liu ◽  
Alexey Dimov ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Volume Growth ◽  
Artery Occlusion ◽  
Blood Pressure Elevation ◽  
And Control ◽  
Cerebral Artery Occlusion

BackgroundThis study sought to test the hypothesis that simultaneous central blood pressure elevation and potent vasodilation can mitigate pial collateral-dependent infarct growth in acute ischemic stroke.MethodsTwenty mongrel canines (20–30 kg) underwent permanent middle cerebral artery occlusion (MCAO). Eight subjects received continuous infusion of norepinephrine (0.1–1.5200 µg/kg/min; titrated to a median of 34 mmHg above baseline mean arterial pressure) and hydralazine (20 mg) starting 30 min following MCAO. Pial collateral recruitment was scored prior to treatment and used to predict infarct volume based on a previously reported parameterization. Serial diffusion magnetic resonance imaging (MRI) acquisitions tracked infarct volumes over a 4-hour time frame. Infarct volumes and infarct volume growth between treatment and control groups were compared with each other and to predicted values. Fluid-attenuated inversion recovery (FLAIR) MRI, susceptibility weighted imaging (SWI), and necropsy findings were included in the evaluation.ResultsDifferences between treatment and control group varied by pial collateral recruitment based on indicator-variable regression effects analysis with interaction confirmed by regression model fit. Benefit in treatment group was only in subjects with poor collaterals which had 35.7% less infarct volume growth (P=0.0008; ANOVA) relative to controls. Measured infarct growth was significantly lower than predicted by the model (linear regression partial F-test, slope P<0.001, intercept=0.003). There was no evidence for cerebral hemorrhage or posterior reversible encephalopathy syndrome.ConclusionOur results indicate that a combination of norepinephrine and hydralazine administered in the acute phase of ischemic stroke mitigates infarct evolution in subjects with poor but not good collateral recruitment.

scholarly journals A Novel Na + -K + -Cl − Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke

Stroke ◽  
2019 ◽  
Vol 50 (4) ◽  
pp. 1021-1025 ◽  
Author(s):  
Huachen Huang ◽  
Mohammad Iqbal H. Bhuiyan ◽  
Tong Jiang ◽  
Shanshan Song ◽  
Sandhya Shankar ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Large Vessel ◽  
Neurological Deficits ◽  
Ang Ii ◽  
Cerebral Artery Occlusion

Background and Purpose— Inhibition of brain NKCC1 (Na + -K + -Cl − cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods— Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)–induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results— Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II–induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions— The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.

scholarly journals Effect of Methylene Blue on White Matter Injury after Ischemic Stroke

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Quancheng Cheng ◽  
Xuhao Chen ◽  
Jiayi Ma ◽  
Xingyuan Jiang ◽  
Jiahui Chen ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Ischemic Stroke ◽  
White Matter ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
White Matter Injury ◽  
Behavioral Deficits ◽  
Cerebral Artery Occlusion

Methylene blue, the FDA-grandfathered drug was proved to be neuroprotective in ischemic stroke in rat. However, the mechanism of the protective effect was unknown. In this study, we used different animal models to investigate the effect of MB administration given within and beyond the therapeutic time window on behavioral deficits and infarct volume and related mechanism about the white matter protection. Middle cerebral artery occlusion and reperfusion (MCAO) and photothrombotic middle cerebral artery occlusion (PT-MCAO) models were used. Behavioral deficits and infarct volume were measured by foot fault test, Garcia neurological score, and TTC staining. Black gold staining and western blot were used to evaluate the brain white matter injury. We found that intraperitoneal administration of MB immediately or 24 h after the MCAO or PT-MCAO surgery reduced infarct volume, improved the neurological deficits, and reduced the white matter injury via myelin basic protein (BMP) protection. These findings suggested that MB relieved the white matter injury besides neuronal protection and has potential therapeutic effects on ischemic stroke.

scholarly journals Silencing of lncRNA XLOC_035088 Protects Middle Cerebral Artery Occlusion-Induced Ischemic Stroke by Notch1 Signaling

2020 ◽  
Vol 80 (1) ◽  
pp. 60-70
Author(s):  
Miao Chen ◽  
Feng Wang ◽  
Hairong Wang
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Hippocampal Neurons ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Cerebral Artery Occlusion

Abstract Ischemic stroke represents one of the leading causes of mortality worldwide and especially in developing countries. It is crucial for finding effective therapeutic targets that protect the brain against ischemic injury. Long noncoding RNAs (lncRNAs) have emerged as major regulators of neurological diseases, and clarifying their roles in cerebral ischemic injury may provide novel targets for the treatment of ischemic stroke. We aimed to investigate the role of lncRNA-XLOC_035088 in middle cerebral artery occlusion (MCAO)-induced rat brain injury and oxygen-glucose deprivation (OGD)-reperfusion treated hippocampal neurons. In our findings, we found that XLOC_035088 expression was significantly upregulated in OGD-reperfusion treated hippocampal neurons and in different brain regions of MCAO-treated rats. XLOC_035088 silencing protected against MCAO-induced ischemic brain injury in vivo and OGD-induced hippocampal neuronal apoptosis in vitro. Intrahippocampal silencing of XLOC_035088 significantly decreased brain XLOC_035088 expression, reduced brain infarct size, and improved neurological function through inhibiting NOTCH1 following derepression of presenilin 2 (PSEN2). Taken together, this study provides evidence that the lncRNA XLOC_035088/PSEN2/Notch1 axis is involved in the pathogenesis of ischemic brain injury, and presents a promising therapeutic route for ischemic stroke.

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