Neuroprotective activity of tamoxifen in permanent focal ischemia

2003 ◽  
Vol 99 (1) ◽  
pp. 138-142 ◽  
Author(s):  
Harold K. Kimelberg ◽  
Yiqiang Jin ◽  
Carol Charniga ◽  
Paul J. Feustel
Keyword(s):  
Rat Model ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Neuroprotective Activity ◽  
Therapeutic Window ◽  
Protective Effects ◽  
Content Type ◽  
Mca Occlusion ◽  
Fine Print ◽  
Permanent Focal Ischemia

Object. The authors have previously shown that tamoxifen is effective in protecting brain tissue from ischemic injury in a rat model of reversible focal ischemia. In this study the authors tested whether similar protective effects are found in a rat model of permanent focal ischemia (permanent middle cerebral artery [MCA] occlusion). Methods. Tamoxifen (20 mg/kg) was given either before or at 1, 3, or 6 hours after permanent MCA occlusion in rats, with sustaining doses given every 12 hours thereafter. The median infarct volume measured after 72 hours was 113 mm3 for the vehicle (dimethyl sulfoxide) groups, compared with 31 mm3 for pretreatment, and 14, 27, and 98 mm3 for treatment beginning at 1, 3, and 6 hours, respectively, after permanent MCA occlusion. The infarct reductions in the pretreated and 1- and 3-hour post—MCA occlusion treatment groups were statistically significant (p < 0.05). At 3 hours after permanent MCA occlusion, tamoxifen also significantly reduced the infarct size at a lower dose of 5 mg/kg but not at 1 mg/kg; the same sustaining doses of 5 and 1 mg/kg were given every 12 hours. Conclusions. Tamoxifen is as effective in a permanent model of focal ischemia as it is in the reversible model, and the therapeutic window of 3 hours after initiation of ischemia is identical. This effectiveness is likely due to several properties of the drug, including its known ability to cross the blood—brain barrier. Because tamoxifen has been administered safely in humans for treatment of gliomas at similarly high doses to those used in this study, it may be clinically useful as a treatment for ischemic stroke.

Reduction by delayed hypothermia of cerebral infarction following middle cerebral artery occlusion in the rat: a time-course study

1992 ◽  
Vol 77 (3) ◽  
pp. 438-444 ◽  
Author(s):  
Christopher J. Baker ◽  
Stephen T. Onesti ◽  
Robert A. Solomon
Keyword(s):  
Body Temperature ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Time Course ◽  
Right Hemisphere ◽  
Infarct Volume ◽  
Moderate Hypothermia ◽  
Content Type ◽  
Mca Occlusion ◽  
Fine Print

✓ The effect of hypothermia on neuronal injury following permanent middle cerebral artery (MCA) occlusion in the rat was examined. Moderate hypothermia (body temperature 24°C) was induced before MCA occlusion (0-minute delay group) in six rats, at 30 minutes in eight rats, and at 1 (seven rats), 2 (seven rats), and 3 (nine rats) hours after occlusion. The rats were kept at a 24°C body temperature for 1 hour, then allowed to rewarm over 90 minutes. The animals were sacrificed 24 hours after MCA occlusion, and infarction was visualized by staining of coronal sections with 2,3,5-triphenyltetrazolium chloride. Infarct volumes were compared to matched normothermic control rats (body temperature 36°C). Additional groups of 0-minute delay hypothermic (10 rats) and control animals (nine rats) were sacrificed 72 hours after MCA occlusion to examine the effects of prolonged survival. A significant reduction in the percentage of infarcted right hemisphere was seen in the animals sacrificed after 24 hours with 0-minute, 30-minute, and 1-hour delays in inducing hypothermia (mean ± standard error of the mean: 2.2% ± 0.7%, 4.4% ± 0.9%, and 3.6% ± 1.1%, respectively) as compared to normothermic control rats (10.8% ± 1.5%, p < 0.01 by Student's t-test). In the 2- and 3-hour delay groups, the percentage of infarcted right hemisphere was 17.1% ± 2.4% and 12.0% ± 2.7%, respectively, and no decrease in infarct volume was observed. The 0-minute delay hypothermia group sacrificed after 72 hours also displayed a significant reduction in right hemisphere infarct compared to their respective controls (4.8% vs. 11.7%, p < 0.05). These findings indicate that, in the setting of permanent MCA occlusion, hypothermia markedly decreases brain injury even when its induction is delayed for up to 1 hour after the onset of ischemia. Ischemic damage does not appear to be merely retarded but permanently averted.

Neuroprotection by the stable nitroxide Tempol during reperfusion in a rat model of transient focal ischemia

2000 ◽  
Vol 92 (4) ◽  
pp. 646-651 ◽  
Author(s):  
Ramin Rak ◽  
Daniel L. Chao ◽  
Ryszard M. Pluta ◽  
James B. Mitchell ◽  
Edward H. Oldfield ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Rat Model ◽  
Focal Ischemia ◽  
Artery Occlusion ◽  
Sprague Dawley ◽  
Triphenyltetrazolium Chloride ◽  
Content Type ◽  
Physiological Variables ◽  
Transient Focal Ischemia ◽  
Fine Print

Object. The use of thrombolytic agents in the treatment of stroke has yielded surprisingly modest success, possibly because of reperfusion injury mediated by reactive oxygen species (ROS). Therefore, scavenging ROS may be of therapeutic value in the treatment of stroke. Nitroxides are low-weight superoxide dismutase mimics, which allows them to act as cell-permeable antioxidants. In this study the nitroxide 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl (Tempol) is investigated to determine its ability to reduce reperfusion injury.Methods. Male Sprague—Dawley rats weighing between 280 g and 350 g underwent middle cerebral artery occlusion with an intraluminal suture for 60 minutes. Regional cerebral blood flow, blood pressure, cerebral temperature, and rectal temperature were monitored during the procedure. After reperfusion, the animals were randomized to groups receiving blinded intravenous administration of either Tempol (10 mg/kg; eight animals) or vehicle (eight animals) over the first 20 minutes of reperfusion (Study I). In a second study to determine dose dependency, animals were randomized to groups receiving Tempol (20 mg/kg; eight animals), low-dose Tempol (5 mg/kg; eight animals), or vehicle (eight animals; Study II). The rats were killed after 4 hours of reperfusion, and brain sections were stained with 2,3,5 triphenyltetrazolium chloride. Infarct volumes were measured using digital imaging.Animals receiving Tempol had significantly reduced infarct volumes at doses of 20 mg/kg and 10 mg/kg compared with controls (49.01 ± 18.22% reduction [p = 0.003] and 47.47 ± 34.57 [p = 0.02], respectively). No significant differences in the physiological variables measured were observed between groups.Conclusions. Tempol provides significant neuroprotection after reperfusion in a rat model of transient focal ischemia. These results support the importance of ROS in reperfusion injury and encourage further study of this molecule as a therapeutic agent following thrombolysis.

Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats

1997 ◽  
Vol 87 (4) ◽  
pp. 595-601 ◽  
Author(s):  
Ludmila Belayev ◽  
Raul Busto ◽  
Weizhao Zhao ◽  
James A. Clemens ◽  
Myron D. Ginsberg
Keyword(s):  
Carotid Artery ◽  
Middle Cerebral Artery ◽  
Brain Edema ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Content Type ◽  
Mca Occlusion ◽  
Neurological Score ◽  
Albumin Therapy ◽  
Fine Print

✓ The authors examined the effect of delayed high-concentration albumin therapy on ischemic injury in a highly reproducible model of middle cerebral artery (MCA) occlusion in rats. Male Sprague—Dawley rats weighing 270 to 320 g were anesthetized with halothane and subjected to 120 minutes of temporary MCA occlusion induced by means of a poly-l-lysine—coated intraluminal nylon suture inserted retrograde via the external carotid artery into the internal carotid artery and MCA. The agent (20% human serum albumin [HSA]) or control solution (sodium chloride 0.9%) was administered intravenously at a dosage of 1% of body weight immediately after suture removal following a 2-hour period of MCA occlusion. The animals' neurological status was evaluated during MCA occlusion (at 60 minutes) and daily for 3 days thereafter. The brains were perfusion-fixed, and infarct volumes and brain edema were determined. The HSA significantly improved the neurological score compared with saline at 24 hours after MCA occlusion. The rats treated with HSA also had significantly reduced total infarct volume (by 34%) and brain edema (by 81%) compared with saline-treated rats. There was a strong correlation between hematocrit level and brain edema (p < 0.01), and between total infarct volume or brain edema and neurological score at 24, 48, and 72 hours postinjury (p < 0.0002). These results strongly support the beneficial effect of delayed albumin therapy in transient focal ischemia and indicate its possible usefulness in treating patients with acute ischemic stroke.

Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia

2000 ◽  
Vol 92 (1) ◽  
pp. 91-99 ◽  
Author(s):  
Pil W. Huh ◽  
Ludmila Belayev ◽  
Weizhao Zhao ◽  
Sebastian Koch ◽  
Raul Busto ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
External Carotid Artery ◽  
External Carotid ◽  
Sprague Dawley ◽  
Content Type ◽  
Mca Occlusion ◽  
Neurological Score ◽  
Fine Print

Object. The purpose of this study was to compare the effects of prolonged hypothermia on ischemic injury in a highly reproducible model of middle cerebral artery (MCA) occlusion in rats.Methods. Male Sprague—Dawley rats were anesthetized with halothane and subjected to 120 minutes of temporary MCA occlusion by retrograde insertion of an intraluminal nylon suture coated with poly-l-lysine through the external carotid artery into the internal carotid artery and the MCA. Two levels of prolonged postischemic cranial hypothermia (32°C and 27°C) and one level of intraischemic cranial hypothermia (32°C) were compared with the ischemic normothermia (37°C) condition. Target cranial temperatures were maintained for 3 hours and then gradually restored to 35°C over an additional 2-hour period. The animals were evaluated using a quantitative neurobehavioral battery of tests before inducing MCA occlusion, during occlusion (at 60 minutes postonset in all rats except those in the intraischemic hypothermia group), and at 24, 48, and 72 hours after reperfusion. The rat brains were perfusion fixed at 72 hours after ischemia, and infarct volumes and brain edema were determined. Both intraischemic and postischemic cooling to 32°C led to similar significant reductions in cortical infarct volume (by 89% and 88%, respectively) and total infarct volume (by 54% and 69%, respectively), whereas postischemic cooling to 27°C produced lesser reductions (64% and 49%, respectively), which were not statistically significant. All three hypothermic regimens significantly lessened hemispheric swelling and improved the neurological score at 24 hours. The authors' data confirm that a high degree of histological neuroprotection is conferred by postischemic cooling to 32°C, which is virtually equivalent to that observed with intraischemic cooling to the same level.Conclusions. These results may be relevant to the design of future clinical trials of therapeutic hypothermia for acute ischemic stroke.

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

1996 ◽  
Vol 85 (5) ◽  
pp. 853-859 ◽  
Author(s):  
Arnd Doerfler ◽  
Michael Forsting ◽  
Wolfgang Reith ◽  
Christian Staff ◽  
Sabine Heiland ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Decompressive Craniectomy ◽  
Control Group ◽  
Acute Ischemia ◽  
Vessel Occlusion ◽  
Content Type ◽  
Time Points ◽  
Infarction Size ◽  
Mca Occlusion ◽  
Fine Print

✓ 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 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 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.

The therapeutic window for spinal cord decompression in a rat spinal cord injury model

2005 ◽  
Vol 3 (4) ◽  
pp. 302-307 ◽  
Author(s):  
Christopher B. Shields ◽  
Y. Ping Zhang ◽  
Lisa B. E. Shields ◽  
Yingchun Han ◽  
Darlene A. Burke ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Spinal Stenosis ◽  
Spinal Cord Compression ◽  
Cord Compression ◽  
Therapeutic Window ◽  
Content Type ◽  
Significant Difference ◽  
Cord Injury ◽  
Fine Print

Object. There are no clinically based guidelines to direct the spine surgeon as to the proper timing to undertake decompression after spinal cord injury (SCI) in patients with concomitant stenosis-induced cord compression. The following three factors affect the prognosis: 1) severity of SCI; 2) degree of extrinsic spinal cord compression; and 3) duration of spinal cord compression. Methods. To elucidate further the relationship between varying degrees of spinal stenosis and a mild contusion-induced SCI (6.25 g-cm), a rat SCI/stenosis model was developed in which 1.13- and 1.24-mm-thick spacers were placed at T-10 to create 38 and 43% spinal stenosis, respectively. Spinal cord damage was observed after the stenosis—SCI that was directly proportional to the duration of spinal cord compression. The therapeutic window prior to decompression was 6 and 12 hours in the 43 and 38% stenosis—SCI lesions, respectively, to maintain locomotor activity. A significant difference in total lesion volume was observed between the 2-hour and the delayed time(s) to decompression (38% stenosis—SCI, 12 and 24 hours, p < 0.05; 43% stenosis—SCI, 24 hours, p < 0.05) indicating a more favorable neurological outcome when earlier decompression is undertaken. This finding was further supported by the animal's ability to support weight when decompression was performed by 6 or 12 hours compared with 24 hours after SCI. Conclusions. Analysis of the findings in this study suggests that early decompression in the rat improves locomotor function. Prolongation of the time to decompression may result in irreversible damage that prevents locomotor recovery.

Extracranial-intracranial arterial bypass for middle cerebral artery stenosis and occlusion

1985 ◽  
Vol 62 (6) ◽  
pp. 831-838 ◽  
Author(s):  
Brian T. Andrews ◽  
Norman L. Chater ◽  
Philip R. Weinstein
Keyword(s):  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Slight Reduction ◽  
Content Type ◽  
Perioperative Stroke ◽  
Arterial Bypass ◽  
Mca Occlusion ◽  
Bypass Patency ◽  
Completed Stroke ◽  
Fine Print

✓ Forty-seven patients with middle cerebral artery (MCA) stenosis and 18 patients with MCA occlusion underwent extracranial-intracranial arterial bypass procedures. Patients presented with a history of transient ischemic attacks (TIA's), reversible ischemic neurological deficits, TIA's after initial stroke, stroke-in-evolution, or completed stroke. Angiography revealed that the MCA stenosis ranged from 70% to over 95%. Two patients (4.3%) in the stenosis group had a perioperative stroke (within 30 days of operation). There was no perioperative mortality. In the occlusion group, no patient had a perioperative stroke, and one patient (5.5%) died from a non-neurological disease. The TIA's resolved completely in 90% of the patients with stenosis and in 91.6% of those with occlusion. No patient with MCA stenosis had a late ipsilateral stroke, although five had a contralateral or vertebrobasilar stroke. One patient with MCA occlusion had a late ipsilateral stroke. The bypass patency rate at late follow-up review was 100%. The results of intracranial-extracranial arterial bypass procedures appear to be similar for patients with either stenosis or occlusion of the MCA. Symptomatic relief of TIA's was excellent and, in two patients with progressive stroke-in-evolution, the deficit was stabilized. The incidence of postoperative ipsilateral stroke was low in patients with TIA's alone or with TIA's after an initial stroke, but among patients with completed stroke, improvement was confined to slight reduction in the neurological deficit.

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.

Cerebral protection by intermittent reperfusion during temporary focal ischemia in the rat

1996 ◽  
Vol 85 (5) ◽  
pp. 923-928 ◽  
Author(s):  
Carlos A. David ◽  
Ricardo Prado ◽  
W. Dalton Dietrich
Keyword(s):  
Arterial Occlusion ◽  
Focal Ischemia ◽  
Global Ischemia ◽  
Cerebral Injury ◽  
Histopathological Analysis ◽  
Content Type ◽  
Group I ◽  
Group Ii ◽  
Temporary Clipping ◽  
Fine Print

✓ Temporary arterial occlusion has been routinely used as an adjunct in intracranial aneurysm surgery. This has commonly been performed using a protocol of multiple short periods of occlusion alternating with periods of restoration of normal circulation. Recently, the logical basis of this method has come under scrutiny. There is extensive experimental evidence to suggest that repetitive, brief periods of global ischemia may cause more severe cerebral injury than an equivalent single period of global ischemia. Only recently has this issue begun to be addressed with regard to focal ischemia. Hence, despite the common use of temporary clipping, little experimental data are available regarding the ischemic consequences of temporary arterial occlusion with periods of reperfusion versus uninterrupted temporary occlusion. To investigate this issue, a protocol of occlusion/reperfusion that simulates the temporal profile that occurs during surgery was performed in a rat model of focal ischemia. Sixteen anesthetized Sprague—Dawley rats were divided into two groups. The animals in Group I underwent 60 minutes of uninterrupted middle cerebral artery occlusion and the animals in Group II were subjected to six separate 10-minute occlusion periods with 5 minutes of reperfusion between occlusions. Histopathological analysis was performed 72 hours postischemia. Group I had significantly increased mean infarction volumes (50.0 ± 12.1 mm3) compared to Group II (8.7 ± 3.1 mm3) (p = 0.008). Injuries in Group I occurred in both the cortex and striatum, whereas Group II showed only striatal injuries. Furthermore, the extent of the injuries in Group II was less severe, characterized by ischemic neuronal injury rather than frank infarction. The results indicate that intermittent reperfusion is neuroprotective during temporary focal ischemia and support the hypothesis that intermittent reperfusion is beneficial if temporary clipping is required during aneurysm repair.

S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage

1989 ◽  
Vol 71 (5) ◽  
pp. 727-731 ◽  
Author(s):  
Hans-Göran Hårdemark ◽  
Nils Ericsson ◽  
Zbigniew Kotwica ◽  
Gerd Rundström ◽  
Ib Mendel-Hartvig ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Brain Damage ◽  
Focal Cerebral Ischemia ◽  
Neuron Specific Enolase ◽  
Experimental Models ◽  
Neurological Injury ◽  
Content Type ◽  
Mca Occlusion ◽  
S 100 ◽  
Fine Print

✓ Cerebrospinal fluid (CSF) markers of brain damage are potentially capable of providing quantitative information about the extent of certain neurological injury. The presence of such markers in CSF after brain damage is transient and it is essential to understand their kinetics if they are to be used in clinical practice. In the present study, the CSF concentrations of two neurospecific proteins, S-100 protein and neuron-specific enolase (NSE), were determined in rats before and repeatedly after one of two types of experimental brain damage: traumatic cortical injury and focal cerebral ischemia induced by middle cerebral artery (MCA) occlusion. The two types of experimental brain damage resulted in significant differences in the kinetics of S-100 and NSE concentrations in CSF. Cortical contusion was followed by a rapid increase in both S-100 and NSE and a peak occurred in both after about 7½ hours, at which time the values declined toward normal. A second, smaller peak was seen after about 1½ days. The increase and decrease in S-100 and NSE levels in CSF was slower after MCA occlusion; a peak was seen after 2 to 4 days. Furthermore, S-100 was generally higher than NSE after trauma, whereas after MCA occlusion the NSE concentration was slightly higher than the S-100 value. These results support the use of CSF markers for estimation of the extent of brain damage in experimental models and forms a basis for the understanding of their kinetics, which is important for their use in clinical practice.

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