Endovascular Middle Cerebral Artery Occlusion Research Articles

Abstract P534: Relationship Between rCBF and Pial Collateral Recruitment in Experimental Acute Ischemic Stroke

Purpose: The purpose of this study was to assess the relationship between relative cerebral blood flow (rCBF) by MRI and leptomeningeal collateral recruitment in an experimental acute ischemic stroke model. Methods: This study was approved by the local IACUC. Eight mongrel canines (20-30kg) underwent endovascular middle cerebral artery occlusion (MCAO). Anesthetics were chosen not to interfere with cerebrovascular reactivity. Physiologic parameters were maintained within normal ranges. Pial collateral recruitment was angiographically assessed using a previously published 11-point scale. After the MCAO, subjects underwent DSC and DTI MRI (3T Achieva, Philips Healthcare, Best, Netherlands) in order to derive rCBF and infarct volume by diffusion restriction on mean diffusivity maps. DSC images were imported into Visage software (Visage Imaging; Richmond Australia). The region of interest was drawn on the penumbra and infarct core and corresponding contralateral side. Infarct volume was calculated by using a quantitative voxel-wise threshold by setting a threshold of 1.5 SD relative to normal values based on an ROI drawn to cover the entire contralateral normal hemisphere exclusive of the ventricles. Results: The pial collateral recruitment was strongly correlated with the rCBF on the penumbral region (r 2 = 0.7823, P-value= 0.003), and with the infarct volume measured two hours following occlusion (r 2 = 0.933376, P value= 0.00009.). There was a poor correlation between the pial collateral recruitment and the rCBF ratio on the core region (R 2 =0.4447, p-value= 0.07.) Conclusion: Preliminary data from this study suggests rCBF from the penumbral regions in experimental MCAO has a closer association with pial collateral recruitment relative to rCBF in the core infarct zone. This information has the potential to affect the interpretation of angiographic studies in acute ischemic stroke and underscores the importance of assessing regional differences in rCBF.

Therapeutic efficacy of intra-arterial administration of induced pluripotent stem cells-derived neural progenitor cells in acute experimental ischemic stroke in rats

Aim. Neural progenitor cells (NPC) are used for the development of cell therapies of neurological diseases. Their stereotaxic transplantation in the middle cerebral artery occlusion (MCAO) model imitating ischemic stroke results in symptom aleviation. However, exploration of less invasive transplantation options is essential, because stereotaxic transplantation is a complex procedure and can be applied to humans only by vital indications in a specialized neurological ward. The aim of the present study was to evaluate the efficacy of cell therapy of the experimental ischemic stroke by the intra-arterial transplantation of NPC.Materials and methods. NPC for transplantation (IPSC-NPC) were derived by two-stage differentiation of cells of a stable line of human induced pluripotent stem cells. Stroke modeling in rats was carried out by transitory 90 min endovascular MCAO by a silicon-tipped filament. NPC were transplanted 24 hours after MCAO. Repetitive magnetic resonance tomography of experimental animals was made with the Bruker BioSpin ClinScan tomograph with 7 Tl magnetic field induction. Animal survival rate and neurological deficit (using mNSS standard stroke severity scale) were evaluated at the 1st (before IPSC-NPC transplantation), 7th and 14th day after transplantation. Histological studies were carried out following standard protocols.Results. Intra-arterial transplantation of 7 × 105 IPSC-NPC in 1 ml at a constant 100 l/min rate in case of secured blood flow through the internal carotid artery did not cause brain capillary embolism, additional cytotoxic brain tissue edemas or other complications, while inducing increase of animal survival rate and enhanced revert of the neurological deficit. IPSC-NPC accumulation in brain after intra-arterial infusion was demonstrated. Some cells interacted with the capillary endothelium and probably penetrated through the blood-brain barrier.Conclusion. Therapeutic efficacy of the systemic, intra-arterial administration of NPC in ischemic stroke has been experimentally proven. A method of secure intra-arterial infusion of cell material into the internal carotid artery middle in rats has been developed and tested.

Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia

Vascular dementia (VaD), incorporating cognitive dysfunction with vascular disease, ranks as the second leading cause of dementia in the United States, yet no effective treatment is currently available. The challenge of defining the pathological substrates of VaD is complicated by the heterogeneous nature of cerebrovascular disease and coexistence of other pathologies, including Alzheimer's disease (AD) types of lesion. The use of rodent models of ischemic stroke may help to elucidate the type of lesions that are responsible for cognitive impairment in humans. Endovascular middle cerebral artery (MCA) occlusion in rats is considered to be a convenient and reliable model of human cerebral ischemia. Both sensorimotor and cognitive dysfunction can be induced in the rat endovascular MCA occlusion model, yet sensorimotor deficits induced by endovascular MCA occlusion may improve with time, whereas data presented in this review suggest that in rats this model can result in a progressive course of cognitive impairment that is consistent with the clinical progression of VaD. Thus far, experimental studies using this model have demonstrated a direct interaction of cerebral ischemic damage and AD-type neuropathologies in the primary ischemic area. Further, coincident to the progressive decline of cognitive function, a delayed neurodegeneration in a remote area, distal to the primary ischemic area, the hippocampus, has been demonstrated in a rat endovascular MCA occlusion model. We argue that this model could be employed to study VaD and provide insight into some of the pathophysiological mechanisms of VaD.

NF-κB protects neurons from ischemic injury after middle cerebral artery occlusion in mice

Knowledge about the molecular mechanisms of neuronal survival following ischemia is crucial to the development of therapeutic interventions for victims of stroke. Previous research in our laboratory has implicated nuclear factor-κB (NF-κB) as contributing to neuronal survival in response to toxic or ischemic brain insult, with in vivo models having focused on the rat. To take advantage of genetic alterations available in the mouse, we utilized a murine transient endovascular middle cerebral artery occlusion (MCAO) model to examine the influence of NF-κB on neuronal survival. When brains were immunostained for the nuclear localization sequence (NLS) of the p50 subunit of NF-κB, a unilateral increase in immunoreactivity was seen, especially in pyramidal cell layers of the ipsilateral (stroked) hippocampus. When transgenic mice lacking p50 were compared with non-transgenic counterparts using Fluoro-Jade, a marker for neurodegeneration, both the hippocampus and striatum showed enhanced neurodegeneration at various survival times after 1 h of MCAO. In the hippocampus specifically, there was an eightfold increase in Fluoro-jade staining in the p50 knockout group vs. the non-transgenic group. Sections double stained for Fluoro-Jade and NF-κB activity (using a mouse engineered with a NF-κB responsive promoter driving a LacZ gene to produce beta galactosidase) demonstrated neuronal degeneration only in regions sparsely showing NF-κB activity, and those demonstrating NF-κB activity failed to degenerate. These data provide evidence that NF-κB participates in survival signaling following temporary focal ischemia, and thus may represent an attractive target for pharmacologic activation in the treatment of stroke.

Cyclooxygenase-1 gene knockout does not alter middle cerebral artery occlusion in a mouse stroke model

Cyclooxygenase (COX) is crucial in inflammation; COX-1 is constitutional, and COX-2 is inducible. In this study, neurological function and infarct volume were evaluated at 24 h after permanent endovascular middle cerebral artery occlusion (MCAO) in both COX-1-gene knockout (homozygous or heterozygous) and wide-type mice. Similar infarct volumes and neurological deficits were seen among mice of different genotypes. There was no difference among the groups in arterial blood pressure and regional cerebral blood flow during the first 30 min of ischemia. Our results failed to confirm the harmful effect of losing COX-1 activity due to gene knockout in a permanent endovascular MCAO mouse stroke model.

Pretreatment with melatonin reduces volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model.

Melatonin is a potent scavenger of free radicals and an indirect antioxidant. Recent studies have shown that melatonin possesses beneficial effects in experimental models of brain trauma and global cerebral ischemia. The effects of pretreatment with melatonin on volume of cerebral infarction were investigated in the present study. Adult male Sprague-Dawley rats were anesthetized with sodium pentobarbital to undergo right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hr. A single dose of melatonin (1.5, 5, 15, or 50 mg/kg in 1 mL normal saline) or its vehicle was given via an intraperitoneal injection at 0.5 hr before MCAO. Relative infarction volumes on day 3 after MCAO were significantly reduced in the groups treated with melatonin at 5 (mean +/- S.E.M., 15.7 +/- 2.5%) or 15 (21.4 +/- 3.1 %) mg/kg but not at 1.5 (30.6 +/- 3.5%) or 50 (26.7 +/- 2.8%) mg/ kg when compared with the vehicle group (33.9 +/- 3.5%). There was no significant difference in the arterial blood pressure (BP), heart rate (HR) and relative cerebral blood flow among the experimental groups. These results indicate that pretreatment with melatonin at a dose between 5 and 15 mg/kg protects against focal cerebral ischemia.

Neuropeptide Y-Y1 receptor modulates nitric oxide level during stroke in the rat

In a rat endovascular middle cerebral artery occlusion (MCAO) stroke model, we previously showed that intracerebroventricular (ICV) injection of neuropeptide Y (NPY) or an Y1 receptor agonist, [Leu 31,Pro 34]-NPY, increased the infarct volume, that an Y1 receptor antagonist, BIBP3226, reduced the infarct volume, and that an Y2 receptor agonist, NPY3-36, had no effect. In this study, we used electron paramagnetic resonance (EPR) spectroscopy to measure nitric oxide (NO) and examined how ICV administration of NPY or its receptor analogs would modulate the brain NO level between the bregma levels +2 and −4 mm during MCAO, since excessive NO mediates ischemic damage. The relative brain NO concentration was increased to 131.94 ± 7.99% (mean ± SEM; n = 8) at 15 min of MCAO. NPY treatment further increased the relative brain NO concentration to 250.94 ± 50.48% ( n = 8), whereas BIBP3226 significantly reduced the brain NO concentration to 69.63 ± 8.84% ( n = 8). [Leu 31,Pro 34]-NPY (137.61 ± 14.54%; n = 7) or NPY3-36 (129.23 ± 21.77%; n = 8) did not affect the brain NO concentration at 15 min of MCAO. Our results suggest that the NPY-Y1 receptor activation mediates ischemic injury via NO overproduction and that inhibition of the Y1 receptor may confer protection via suppression of excessive NO production during ischemia.

Decompressive craniectomy in a rat model of "malignant" cerebral hemispheric stroke: experimental support for an aggressive therapeutic approach.

Acute ischemia in the complete territory of the carotid artery may lead to massive cerebral edema with raised intracranial pressure and progression to coma and death due to uncal, cingulate, or tonsillar herniation. Although clinical data suggest that patients benefit from undergoing decompressive surgery for acute ischemia, little data about the effect of this procedure on experimental ischemia are available. In this article the authors present results of an experimental study on the effects of decompressive craniectomy performed at various time points after endovascular middle cerebral artery (MCA) occlusion in rats. Focal cerebral ischemia was induced in 68 rats using an endovascular occlusion technique focused on the MCA. Decompressive craniectomy was performed in 48 animals (in groups of 12 rats each) 4, 12, 24, or 36 hours after vessel occlusion. Twenty animals (control group) were not treated by decompressive craniectomy. The authors used the infarct volume and neurological performance at Day 7 as study endpoints. Although the mortality rate in the untreated group was 35%, none of the animals treated by decompressive craniectomy died (mortality 0%). Neurological behavior was significantly better in all animals treated by decompressive craniectomy, regardless of whether they were treated early or late. Neurological behavior and infarction size were significantly better in animals treated very early by decompressive craniectomy (4 hours) after endovascular MCA occlusion (p < 0.01); surgery performed at later time points did not significantly reduce infarction size. The results suggest that use of decompressive craniectomy in treating cerebral ischemia reduces mortality and significantly improves outcome. If performed early after vessel occlusion, it also significantly reduces infarction size. By performing decompressive craniectomy neurosurgeons will play a major role in the management of stroke patients.

Decompressive craniectomy in a rat model of “malignant” cerebral hemispheric stroke: experimental support for an aggressive therapeutic approach

Acute ischemia in the complete territory of the carotid artery may lead to massive cerebral edema with raised intracranial pressure and progression to coma and death due to uncal, cingulate, or tonsillar herniation. Although clinical data suggest that patients benefit from undergoing decompressive surgery for acute ischemia, little data about the effect of this procedure on experimental ischemia are available. this article the authors present results of an experimental study on the effects of decompressive craniectomy performed at various time points after endovascular middle cerebral artery (MCA) occlusion in rats. Focal cerebral ischemia was induced in 68 rats using an endovascular occlusion technique focused on the MCA. Decompressive cranioectomy was performed in 48 animals (in groups of 12 rats each) 4, 12, 24, or 36 hours after vessel occlusion. Twenty animals (control group) were not treated by decompression craniectomy. The authors used the infarct volume and neurological performance at Day 7 as study endpoints. Although the mortality rate in the untreated group was 35%, none of the animals treated by decompressive craniectomy died (mortality 0%). Neurological behavior was significantly better in all animals treated by decompressive craniectomy, regardless of whether they were treated early or late. Neurological behavior and infarction size were significantly better in animals treated very early by decompressive craniectomy (4 hours) after endovascular MCA occlusion (p less than 0.01); surgery performed at later time points did not significantly reduce infarction size. The results suggest that use of decompressive craniectomy in treating cerebral ischemia reduces mortality and significantly improves outcome. If performed early after vessel occlusion, it also significantly reduces infarction size. By performing decompressive craniectomy neurosurgeons will play a major role in the management of stroke patients.

Induced hypertension during ischemia reduces infarct area after temporary middle cerebral artery occlusion in rats

Induced hypertension is one of the few interventions available to reverse acute ischemic neurologic deficit. The purpose of this study was to determine the safety and efficacy of hypertension during prolonged temporary focal ischemia. Anesthetized rats underwent 2 hours of endovascular middle cerebral artery occlusion. Angiotensin was given to increase mean arterial blood pressure to 40%-60% above baseline during ischemia. Neurologic deficit and infarct size in hypertensive rats were assessed at 72 hours. Hypertensive rats had smaller infarcts than normotensive controls (mean, 12.40 +/- 3.71% versus 24.19 +/- 2.89; p < 0.05) without hemorrhage. Neuroscores were comparable. Hypertension safely reduces infarction after 2 hours of focal ischemia in rats.

Diffusion-weighted magnetic resonance imaging during brief focal cerebral ischemia and early reperfusion: Evolution of delayed infarction in rats

The purpose of this study was to ascertain if the signal intensity ratio and the lesion area determined by diffusion-weighted magnetic resonance imaging during brief focal ischemia and early reperfusion predict outcome determined by diffusion-weighted magnetic resonance imaging and T2-magnetic resonance imaging at 24 h. Seventeen rats were imaged before and during 30 min of endovascular middle cerebral artery occlusion and at 15 min, and 23.5 h after the onset of reperfusion. Both hemisphere and basal ganglia signal intensity ratio increased significantly from baseline during ischemia, decreased significantly from ischemic levels during early reperfusion, and increased again at 24 h. However, signal intensity ratio during ischemia or after 45 min of reperfusion did not correlate statistically with diffusion-weighted-signal intensity ratio at 24 h. Both hemisphere signal intensity ratio and basal ganglia signal intensity ratio at 15 min of reperfusion correlated, but only moderately, with diffusion-weighted-signal intensity ratio at 24 h (r = 0.52, p < or = 0.05). Although lesion areas during ischemia were comparable to those observed at 24 h, lesion areas at both 15 and 45 min of reperfusion were significantly smaller than those observed during ischemia and at 24 hr. Thus, sequential imagining demonstrated partial resolution and delayed recurrence of magnetic resonance-defined ischemic lesions during reperfusion after brief focal ischemia.