Tamoxifen as an effective neuroprotectant in an endovascular canine model of stroke

2011 ◽  
Vol 114 (4) ◽  
pp. 1117-1126 ◽  
Author(s):  
Alan S. Boulos ◽  
Eric M. Deshaies ◽  
John C. Dalfino ◽  
Paul J. Feustel ◽  
A. John Popp ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Infarct Size ◽  
Vertebral Artery ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Randomized Study ◽  
Neurological Deficits ◽  
Large Animal Model ◽  
Large Animal ◽  
The Mean

Object Tamoxifen has been shown to be a potent neuroprotectant against stroke in rodents. Because other neuroprotectant medications have failed in human trials, a study of tamoxifen in a large-animal model was necessary to further assess the drug's effectiveness. For this study, the authors developed an endovascular model of anterior circulation infarction in canines to mimic the human clinical condition. They assessed the following hypotheses: 1) that they will be able to consistently produce an internal carotid artery (ICA) terminus infarction and 2) that tamoxifen is an effective neuroprotectant against stroke in canines. Methods In 24 male beagles (weight 9–11 kg), bilateral femoral artery cutdowns were performed, and the vertebral artery and left ICA were each selectively catheterized. Under fluoroscopic guidance, a microcatheter was introduced via the vertebral artery, guiding the catheter into the basilar artery, posterior communicating artery, and ICA terminus. A 1-ml clot was injected in the terminus, occluding the middle cerebral artery (MCA) and anterior cerebral artery (ACA) origin. In the first 12 canines, the occlusions were confirmed by angiography. A Canine Stroke Score (CSS) was assigned (score range 0–18 [0 = intact on examination, 18 = comatose]). The animals were then killed and their brains stained with 2,3,5-triphenyltetrazolium chloride (TTC). The subsequent 12 canines underwent a blinded randomized study in which the authors compared the results of tamoxifen (5 mg/kg) infused intravenously 1 hour after clot injection with an equal volume of vehicle (dimethylsulfoxide). After 3 hours, the animals underwent MR imaging, were extubated, and clinical examinations were performed. The canines were killed at 8 hours after clot injection, and TTC staining was used. Results In the first group, infarct volume and CSSs were consistent with the extent of the occlusion of the angiographic vessels. An occlusion of the ACA, MCA, and posterior cerebral artery resulted in larger infarcts and higher stroke scores than occlusion of the ACA and MCA. In the second group, tamoxifen significantly reduced infarct size and improved clinical outcomes. In tamoxifen-treated animals, the mean infarct volume reduction was 40% (p < 0.05) and the mean CSS was significantly less than vehicle-treated animals (p < 0.001). There were significant correlations among MR imaging-determined volume, TTC-determined volume, and neurological clinical outcome (p < 0.05). Conclusions Using this endovascular model of stroke, the authors were able to consistently produce an infarction in the canines that was similar in scope to a carotid terminus occlusion in humans. Also, angiography could predict subsequent clinical course and infarct size. Tamoxifen was effective at significantly improving the canine neurological deficits and reducing the size of the stroke. This study took the first step in demonstrating the effectiveness of a promising human neuroprotectant in a large animal.

Proximal occlusion of the middle cerebral artery in C57Black6 mice: relationship of patency of the posterior communicating artery, infarct evolution, and animal survival

2004 ◽  
Vol 100 (1) ◽  
pp. 97-105 ◽  
Author(s):  
Kazuhide Furuya ◽  
Nobutaka Kawahara ◽  
Kensuke Kawai ◽  
Tomikatsu Toyoda ◽  
Keiichiro Maeda ◽  
...  
Keyword(s):  
Survival Rate ◽  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Posterior Communicating Artery ◽  
Neurological Deficits ◽  
Content Type ◽  
Fine Print

Object. The intraluminal suture model for focal cerebral ischemia is increasingly used, but not without problems. It causes hypothalamic injury, subarachnoid hemorrhage, and inadvertent premature reperfusion. The patency of the posterior communicating artery (PCoA) potentially affects the size of the infarct. In addition, survival at 1 week is unstable. The authors operated on C57Black6 mice to produce proximal middle cerebral artery occlusion (MCAO) so that drawbacks with the suture model could be circumvented. Methods. The MCA segment just proximal to the olfactory branch was occluded either permanently or temporarily. After 1 hour of MCAO the infarct volume was significantly smaller than that found after 2 hours or in instances of permanent MCAO. The differences were assessed at 24 hours and 7 days after surgery (p < 0.05 and p < 0.001, respectively). The patency of the PCoA, as visualized using carbon black solution, did not correlate with the infarct size. Neurologically, the 1- and 2-hour MCAO groups displayed significantly less severe deficits than the permanent MCAO group on Days 1, 4, and 7 (p < 0.005 and p < 0.01, respectively). Although the infarct size, neurological deficits, and body weight loss were more severe in the permanent MCAO group, the survival rate at Day 7 was 80%. Conclusions. This model provides not only a robust infarct size (which is not affected by the patency of the PCoA), but also a better survival rate.

Association of Infarct Volume Before Hemicraniectomy and Outcome After Malignant Infarction

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011987
Author(s):  
Dominik Lehrieder ◽  
Katharina Layer ◽  
Hans-Peter Müller ◽  
Viktoria Rücker ◽  
Jan Kassubek ◽  
...  
Keyword(s):  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Randomized Trials ◽  
Infarct Volume ◽  
Unfavorable Outcome ◽  
Inclusion Criteria ◽  
Younger Patients ◽  
Malignant Infarction ◽  
The Impact

ObjectiveTo determine the impact of infarct volume before hemicraniectomy in malignant middle cerebral artery infarction (MMI) as an independent predictor for patient selection and outcome prediction, we retrospectively analyzed data of 140 patients from a prospective multi-center study.MethodsPatients from the DESTINY-Registry that underwent hemicraniectomy after ischemic infarction of >50% of the middle cerebral artery territory were included. Functional outcome according to the modified Rankin Scale (mRS) was assessed at 12 months. Unfavorable outcome was defined as mRS 4-6. Infarct size was quantified semi-automatically from computed tomography or magnetic resonance imaging before hemicraniectomy. Subgroup analyses in patients fulfilling inclusion criteria of randomized trials in younger patients (age≤60y) were predefined.ResultsAmong 140 patients with complete datasets (34% female, mean (SD) age 54 (11) years), 105 (75%) had an unfavorable outcome (mRS > 3). Mean (SD) infarct volume was 238 (63) ml. Multivariable logistic regression identified age (OR 1.08 per 1 year increase; 95%-CI 1.02-1.13; p=0.004), infarct size (OR 1.27 per 10ml increase; 95%-CI 1.12-1.44; p<0.001) and NIHSS (OR 1.10; 95%-CI 1.01-1.20; p=0.030) before hemicraniectomy as independent predictors for unfavorable outcome. Findings were reproduced in patients fulfilling inclusion criteria of randomized trials in younger patients. Infarct volume thresholds for prediction of unfavorable outcome with high specificity (94% in overall cohort and 92% in younger patients) were more than 258 ml before hemicraniectomy.ConclusionOutcome in MMI strongly depends on age and infarct size before hemicraniectomy. Standardized volumetry may be helpful in the process of decision making concerning hemicraniectomy.

Acute Middle Cerebral Artery Occlusion: Experience with Volume Expansion Therapy

Neurosurgery ◽  
1986 ◽  
Vol 18 (4) ◽  
pp. 397-401 ◽  
Author(s):  
Bruce I. Tranmer ◽  
Cordell E. Gross ◽  
Ted S. Keller ◽  
Glenn W. Kindt
Keyword(s):  
Cardiac Output ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Volume Expansion ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Life Styles ◽  
Arterial Blood ◽  
Mca Occlusion ◽  
The Mean

Abstract Five consecutive patients with acute neurological deficits after middle cerebral artery (MCA) occlusion were given emergency treatment with colloidal volume expansion. In each case, the diagnosis was confirmed promptly by computed tomography and cerebral angiography. Aggressive volume expansion therapy was started 2 to 18 hours (mean, 11 hr) after the onset of the neurological deficit. The mean colloidal volume used was 920 ml/day for an average of 4 days. During volume expansion, the mean cardiac output increased 57% from 4.6 + 0.6 to 7.2 + 1.9 litres/min (P &lt; 0.05). The mean hematocrit decreased 19% from 46 + 3% to 37 + 4% (P &lt; 0.01). The mean arterial blood pressure remained stable, and the pulmonary artery wedge pressure was maintained at &lt; 15 mm Hg. Three patients improved dramatically with volume expansion therapy and have returned to their previous life-styles. Two patients made partial recoveries and manage at home with nursing care. The three patients who improved dramatically were young (aged &lt;34) and, when compared to the older patients, they had greater increases in cardiac output (67% vs. 19%). No major complications or deaths were attributed to the volume expansion therapy. We propose that intravascular volume expansion and its concomitant augmentation of the cardiovascular dynamics may be effective in the treatment of acute neurological deficits after acute MCA occlusion.

scholarly journals Infarct Evolution in a Large Animal Model of Middle Cerebral Artery Occlusion

2019 ◽  
Vol 11 (3) ◽  
pp. 468-480 ◽  
Author(s):  
Mohammed Salman Shazeeb ◽  
Robert M. King ◽  
Olivia W. Brooks ◽  
Ajit S. Puri ◽  
Nils Henninger ◽  
...  
Keyword(s):  
Animal Model ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Artery Occlusion ◽  
Large Animal Model ◽  
Large Animal ◽  
Cerebral Artery Occlusion

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.

Abstract TP107: Midline Shift Predicts Functional Outcomes in Porcine Ischemic Stroke Model

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Samantha Spellicy ◽  
Erin Kaiser ◽  
Michael Bowler ◽  
Brian Jurgielewicz ◽  
Robin Webb ◽  
...  
Keyword(s):  
Animal Model ◽  
Ischemic Stroke ◽  
Functional Outcomes ◽  
Randomized Study ◽  
Large Animal Model ◽  
Control Group ◽  
Large Animal ◽  
Midline Shift ◽  
Post Stroke ◽  
Significant Difference

In this study, we sought to identify acute MRI parameters which are predictive of long-term functional outcomes as well as assess the effects of a neural stem cell extracellular vesicle (NSC EV) therapeutic in a large animal model of ischemic stroke. In this randomized study, stroke was induced through a permanent right-sided middle cerebral artery occlusion (MCAO) on 16 male landrace pigs, which were divided into either treatment or control group. NSC EVs or PBS was administered at 2, 14, and 24 hours, and MRI was conducted at day 1 and 84 post-stroke. Data on 65 gait and 25 behavior parameters were collected pre-stroke and at multiple timepoints over 84 days following MCAO. Of all 15 measured MRI parameters, axial and coronal midline shift (MLS), at day 1 post stroke, had the highest total number of significant correlations (52 parameters at p<0.05) to acute and chronic functional measurements in control animals such as step time in the left front limb (p=0.0322) and cycle time in the right hind limb (p=0.0011) respectively. This suggests MLS is the best overall predictor of specific functional deficits at both acute and chronic timepoints, which to our knowledge has never been shown in an animal model. Additionally, the parameters found to be correlated to MLS in control animals were not correlated in NSC EV-treated animals, suggesting NSC EV treatment disrupts this natural correlation between degree of MLS and functional outcomes. NSC EVs and control pigs were binned into either high or low MLS groups and their survival and recovery was assessed by the modified Rankin Scale (mRS). While there was a significant difference in mRS scores of control animals with high and low MLS at day 6 post-MCAO (p=0.0008), there was not in NSC EV-treated animals (p=0.6754). Further, there was a significant difference in survival of control animals with high and low axial MLS (p=0.0401), but not in the NSC EV group (p=0.4142). Additionally, mRNA expression of GFAP was significantly correlated with increasing MLS in non-treated but not NSC EV-treated animals. These findings show although NSC EV treatment does not significantly alter the degree of MLS 1-day post-MCAO, it does alter gene expression, increase survival, and improve functional recovery following large MLS alterations.

Robotic-Assisted Endoscopic Thoracic Aortic Anastomosis in Juvenile Lambs

2005 ◽  
Vol 6 (1) ◽  
pp. 38 ◽  
Author(s):  
Sunil P. Malhotra ◽  
David Le ◽  
Stephan Thelitz ◽  
Frank L. Hanley ◽  
R. Kirk Riemer ◽  
...  
Keyword(s):  
Artery Bypass ◽  
Surgical Techniques ◽  
Lung Ventilation ◽  
Large Animal Model ◽  
Burst Pressure ◽  
Computer Assisted ◽  
Large Animal ◽  
Robotic Assisted ◽  
The Mean ◽  
Aortic Anastomosis

<P>Background: Advances in robotic technology have enabled a wider range of applications for minimally invasive techniques in cardiac surgery, including mitral valve repair and coronary artery bypass grafting. With increased technical sophistication, robotic-assisted techniques can be developed for the endoscopic repair of certain congenital cardiac lesions. </P><P>Objective: The purpose of this study was to assess the feasibility of closed chest thoracic aortic anastomosis in a juvenile ovine model. </P><P>Methods: Lambs, aged 45 to 55 days, underwent surgery that was performed using the da Vinci robotic surgical system. Using 3 ports, the surgeon dissected the descending thoracic aorta and mobilized it free from attachments, using single-lung ventilation and CO<SUB>2</SUB> insufflation. Snares were introduced through 2 stab wounds for aortic occlusion proximally and distally. In 4 lambs, the aorta was completely transected and reanastomosed using interrupted nitinol sutures. One lamb underwent longitudinal aortotomy, and patch aortoplasty was performed with the placement of a Gore-Tex patch. Snares were released and the animals were recovered once hemodynamically stable. Animals were sacrificed at 6 to 12 hours after surgery and the descending aorta was harvested. Burst-pressure testing was performed on the anastomoses. </P><P>Results: All 5 lambs survived the procedure with stabilization of hemodynamic parameters following surgery. The mean aortic clamp time was 47 � 17 minutes, and the anastomosis was completed in 26 � 5 minutes. The mean burst pressure was 163 � 9 mm Hg. Conclusions: Endoscopic thoracic aortic anastomosis can be performed safely and with adequate exposure in a juvenile large-animal model using computer-assisted surgical techniques. With further refinements, these approaches could be applied to the repair of congenital anomalies of the aorta, including interrupted aortic arch and aortic coarctation.</P>

Gamma Knife surgery for basal ganglia and thalamic arteriovenous malformations

2012 ◽  
Vol 116 (4) ◽  
pp. 899-908 ◽  
Author(s):  
Ching-Hsiao Cheng ◽  
R. Webster Crowley ◽  
Chun-Po Yen ◽  
David Schlesinger ◽  
Mark E. Shaffrey ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Mr Imaging ◽  
Gamma Knife ◽  
Treatment Option ◽  
Arteriovenous Malformations ◽  
Gamma Knife Surgery ◽  
Neurological Deficits ◽  
Cerebral Arteriovenous Malformations ◽  
History Of ◽  
The Mean

Object Gamma Knife surgery (GKS) has emerged as the treatment of choice for small- to medium-sized cerebral arteriovenous malformations (AVMs) in deep locations. The present study aims to investigate the outcomes of GKS for AVMs in the basal ganglia and thalamus. Methods Between 1989 and 2007, 85 patients with AVMs in the basal ganglia and 97 in the thalamus underwent GKS and were followed up for more than 2 years. The nidus volumes ranged from 0.1 to 29.4 cm3 (mean 3.4 cm3). The mean margin dose at the initial GKS was 21.3 Gy (range 10–28 Gy). Thirty-six patients underwent repeat GKS for residual AVMs at a median 4 years after initial GKS. The mean margin dose at repeat GKS was 21.1 Gy (range 7.5–27 Gy). Results Following a single GKS, total obliteration of the nidus was confirmed on angiograms in 91 patients (50%). In 12 patients (6.6%) a subtotal obliteration was achieved. No flow voids were observed on MR imaging in 14 patients (7.7%). Following single or repeat GKS, total obliteration was angiographically confirmed in 106 patients (58.2%) and subtotal obliteration in 8 patients (4.4%). No flow voids on MR imaging were observed in 18 patients (9.9%). The overall obliteration rates following one or multiple GKSs based on MR imaging or angiography was 68%. A small nidus volume, high margin dose, low number of isocenters, and no history of embolization were significantly associated with an increased rate of obliteration. Twenty-one patients experienced 25 episodes of hemorrhage in 850 risk-years following GKS, yielding an annual hemorrhage rate of 2.9%. Four patients died in this series: 2 due to complications of hemorrhage and 2 due to unrelated diseases. Permanent neurological deficits caused by radiation were noted in 9 patients (4.9%). Conclusions Gamma Knife surgery offers a reasonable chance of obliterating basal ganglia and thalamic AVMs and does so with a low risk of complications. It is an optimal treatment option in patients for whom the anticipated risk of microsurgery is too high.

scholarly journals Effect of 20-HETE Inhibition on Infarct Volume and Cerebral Blood Flow after Transient Middle Cerebral Artery Occlusion

2008 ◽  
Vol 29 (3) ◽  
pp. 629-639 ◽  
Author(s):  
Marija Renic ◽  
Judith A Klaus ◽  
Tomohiro Omura ◽  
Naoya Kawashima ◽  
Michihito Onishi ◽  
...  
Keyword(s):  
At Risk ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Dienoic Acid ◽  
Artery Occlusion ◽  
Area At Risk

This study examined the effects of an inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis, N-(3-chloro-4-morpholin-4-yl)phenyl- N'-hydroxyimido formamide (TS-011), on infarct volume, volume at risk, cerebral blood flow (CBF), and levels of cytochrome P450 (CYP450) eicosanoids in the brain after transient occlusion of the middle cerebral artery (t-MCAO) in rats. TS-011 (0.1 mg/kg, iv) reduced cortical infarct volume by approximately 70% and total infarct volume by 55%. TS-011 had no effect on the volume at risk or CBF during or up to 30 mins after the ischemic period. TS-011 reduced the delayed fall in CBF seen 2 h after reperfusion. The levels of CYP450 eicosanoids were similar in the ischemic and contralateral hemispheres after t-MCAO. TS-011 reduced 20-HETE levels in cerebral tissue by 80% but had no effect on the levels of EETs. Administration of another 20-HETE inhibitor, HET0016 (0.01 to 1.0 mg/kg, iv) or a 20-HETE antagonist 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid (10 mg/kg, iv) also reduced infarct size. These results indicate that inhibitors of the synthesis or vasoconstrictor effects of 20-HETE reduce infarct size in rats after cerebral ischemia. The effects of TS-011 are not associated with changes in the area at risk or CBF and may be because of a potential protective effect in neurons subjected to ischemic stress.

Treatment and outcome in 30 patients with posterior cerebral artery aneurysms

2003 ◽  
Vol 99 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Christopher L. Taylor ◽  
Thomas A. Kopitnik ◽  
Duke S. Samson ◽  
Phillip D. Purdy
Keyword(s):  
Visual Field ◽  
Cerebral Artery ◽  
Posterior Cerebral Artery ◽  
Underlying Disease ◽  
Neurological Deficits ◽  
Content Type ◽  
Ruptured Aneurysms ◽  
The Mean ◽  
Poor Outcomes ◽  
Fine Print

Object. The records of 30 patients with posterior cerebral artery (PCA) aneurysms treated during a 12-year period were reviewed to determine outcome and the risk of visual field deficit associated with PCA sacrifice. Methods. Clinical data and treatment summaries for all patients were maintained in an electronic database. The Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) scores were determined by an independent registrar. Visual field changes were determined by review of medical records. Twenty-eight patients were treated with open surgery, one of them after an attempt at detachable coil embolization failed. Two patients underwent successful endovascular PCA sacrifice. The mean GOS and mRS scores in 18 patients with unruptured aneurysms were 4 and 2, respectively, at discharge. Subarachnoid hemorrhage (SAH) from other aneurysms and neurological deficits caused by the PCA lesion or underlying disease contributed to poor outcomes in this group. The mean GOS and mRS scores in 12 patients with ruptured aneurysms were 4 and 4, respectively, at discharge. One patient died of severe vasospasm. Neurological deficits secondary to SAH and, in one patient, treatment of a concomitant arteriovenous malformation contributed to poor outcomes in the patients with ruptured aneurysms. Seven patients with normal visual function preoperatively underwent PCA occlusion. One patient (14%) developed a new visual field deficit. Conclusions. Optimal treatment of PCA aneurysms is performed via one of several surgical approaches or by endovascular therapy. The approach is determined, in part, by the anatomical location and size of the aneurysm and the presence of underlying disease and neurological deficits.

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