(Stroke. 1996;27:1616-1623.)
© 1996 American Heart Association, Inc.
Articles |
Middle Cerebral Artery Occlusion in the Rat by Intraluminal Suture
Neurological and Pathological Evaluation of an Improved Model
the Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami School of Medicine, Miami, Fla.
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Abstract |
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Background and Purpose The purpose of the present study was to evaluate a modified method of intraluminal suture occlusion of the middle cerebral artery (MCA) on the volume of brain infarction and on neurobehavioral function in rats subjected to a temporary focal ischemic insult.
Methods Male Sprague-Dawley rats were anesthetized with halothane and subjected to 60 minutes or 2 hours of temporary MCA occlusion (MCAo) by an intraluminal thread. In one group of rats, the suture was coated with poly-L-lysine, while in a second group, a conventional uncoated suture was used. Behavioral function was evaluated at 50 to 60 minutes after occlusion and during a 3-day period after MCAo. Three days after MCAo, brains were perfusion-fixed and infarct volumes were measured.
Results In rats with 60-minute MCAo, only 3 of 7 animals with uncoated sutures had infarcts, whereas in the group with poly-L-lysine–coated sutures, all rats (n=7) exhibited infarction (P=.009, Fisher's exact test). With 2 hours of MCAo, total infarct volume (corrected for brain edema) was significantly larger in rats with poly-L-lysine–coated sutures than in the group with uncoated sutures (mean±SEM, 122.1±4.8 versus 67.0±18.2 mm3, respectively; P=.03; n=4 in each group). In the 2-hour MCAo study, infarct volumes in the uncoated-suture group tended to be variable and inconsistent (coefficient of variation, 54%) compared with the group in which sutures were coated with poly-L-lysine, in which a highly consistent infarct was produced (coefficient of variation of infarct volume, 8%).
Conclusions Reversible MCAo in which a poly-L-lysine–coated intraluminal suture was used proved to be a reliable and effective modification of this technique, yielding consistently larger infarcts and greatly reduced interanimal variability.
Key Words: animal models • middle cerebral artery occlusion • rats • poly-L-lysine
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Introduction |
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The development of reliable and reproducible animal models of cerebral ischemia is required for the systematic study of the pathophysiology and treatment of stroke, the third most common disease-related killer in our society. Desirable animal models are those that replicate features of human cerebrovascular syndromes.1 2 Rat models of focal cerebral ischemia have gained increasing acceptance in recent years owing to their relevance to the human clinical setting.3 MCAo in the rat has been in use since 1975.4 One widely used technique of MCAo involves cauterization of the MCA via a craniotomy5 ; this technique is invasive and does not permit reperfusion. In human ischemic stroke, however, recirculation occurs frequently after focal ischemia, particularly in the case of cerebral embolism.6 In the rat, mechanical clipping of the MCA7 and photothrombotic occlusion of the vessel8 are in common use, but these techniques also involve craniotomy.
In 1986, Koizumi et al9 reported a novel, relatively noninvasive method of achieving reversible MCAo by the use of an intraluminal suture. Subsequently, Zea Longa et al10 reported a variation of this method and stated that their technique reliably produced regional infarcts. Nonetheless, brain injury produced by MCAo in rodents varies considerably in its size and distribution; this variability in infarct volume from animal to animal necessitates the use of large numbers of animals to discern statistical significance in drug testing. We initially adopted the method of Zea Longa et al10 to study focal ischemia in the rat but found that the technique produced inconsistent infarct volume.11 We then chose to coat the sutures used for intraluminal MCAo with poly-L-lysine, a polycationic polymerized amino acid, in order to increase adhesive forces around the suture. Poly-L-lysine has been used to coat glass slides in preparing tissue sections for immunocytochemical staining.12 Since the polycationic poly-L-lysine molecules adsorb strongly to solid surfaces, leaving exposed cationic sites that combine with the anionic sites on cell surfaces,13 we suspected that this might encourage adhesion of the suture to the adjacent vascular endothelium.
In the present study we assessed the success of intraluminal MCAo by both neurobehavioral evaluation and quantitative histopathology. The use of behavioral measures is directly analogous to the clinical neurological examination for assessing ischemic deficits and rates of behavioral recovery in patients.14 Our results indicate that the coated intraluminal suture greatly enhances the consistency of the model and leads to reproducible cerebral infarction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Studies were performed in 25 adult male Sprague-Dawley rats, weighing 280 to 340 g, obtained from Charles River Laboratories, Inc, Wilmington, Mass.
Surgical Preparation
Animals were fasted overnight but were allowed free access to water. Atropine sulfate (0.5 mg/kg IP) was injected 10 minutes before anesthesia. Anesthesia was induced with 3.5% halothane in a mixture of 70% nitrous oxide and 30% oxygen. Rats were orally intubated and mechanically ventilated. During ventilation, the animals were paralyzed with pancuronium bromide (0.6 mg/kg IV). Temperature probes were inserted into the rectum and the left temporalis muscle, and separate heating lamps were used to maintain rectal and cranial temperatures at 37°C to 37.5°C (Mon-a-therm 7000; Mallinckrodt Inc). Polyethylene catheters were introduced into the right femoral artery and vein for blood pressure recording and blood sampling. Rectal temperature and body weight were monitored before MCAo and periodically for 3 days after MCAo. Mean arterial pressure was measured with the use of an indwelling femoral arterial catheter connected to a precalibrated Statham pressure transducer (model P23XL; Viggo-Spectramed, Inc) and was recorded continuously (model RS3400 polygraph; Gould, Inc). Serial measurements were made of arterial blood gases and pH (model ABL 330; Radiometer America, Inc) and plasma glucose (model 2300 Stat; Yellow Springs Instrument Co, Inc).
MCAo was induced as described by Zea Longa et al.10 Under an operating microscope, the right CCA was exposed through a midline neck incision and was carefully dissected free from surrounding nerves and fascia, from its bifurcation to the base of the skull. The occipital artery branches of the ECA were then isolated, and these branches were dissected and coagulated. The ECA was dissected further distally and coagulated along with the terminal lingual and maxillary artery branches, which were then divided. The ICA was isolated and carefully separated from the adjacent vagus nerve, and the pterygopalatine artery was ligated close to its origin with a 5-0 nylon suture. Next, a 5-0 silk suture was tied loosely around the mobilized ECA stump, and a 4-cm length of 3-0 monofilament nylon suture (Harvard Apparatus) was inserted through the proximal ECA into the ICA and thence into the circle of Willis, effectively occluding the MCA. The silk suture around the ECA stump was tightened around the intraluminal nylon suture to prevent bleeding.
Preparation of Suture
We blunted the tip of the suture before it was used by heating it near a flame. In the studies in which a coated suture was used, a 20-mm distal segment of the suture was then coated with poly-L-lysine solution (0.1% [wt/vol], in deionized water; Sigma) and dried in a 60°C oven for 1 hour. The diameter of the suture was not changed by the coating process. The suture was inserted 18 to 20 mm from the bifurcation of the CCA, according to the animal's body weight. After the intraluminal suture was placed, the neck incision was closed with a silk suture.
The animals were then awakened from anesthesia and returned to their cages. Rats that did not demonstrate a right upper extremity paresis during this recovery period were excluded from further study (only one animal from the 60-minute uncoated group was excluded for the above reason). After 60 minutes or 2 hours of MCAo, rats were reanesthetized with the same anesthetic combination. Temperature probes were reinserted, and the intraluminal suture was carefully removed. The CCA and ICA were then inspected to ensure the return of good pulsations. The neck incision was closed with silk suture, and the animals were allowed to survive for 3 days with free access to food and water. Within each series (60-minute and 2-hour MCAo), the rats with uncoated versus poly-L-lysine sutures were completely randomized with each other. Although the 60-minute series was largely performed before the 2-hour series began, these two series were also partially intermixed in time.
Behavioral Testing
Behavioral tests were performed in all 25 rats before MCAo, during MCAo (at 50 or 60 minutes), and daily during the 72-hour observation period by an investigator (L.B.) who was blinded to the experimental groups. The battery consisted of two tests that have been used previously to evaluate various aspects of neurological function: (1) the postural reflex test, developed by Bederson at al15 to examine upper body posture while the animal is suspended by the tail, and (2) the forelimb placing test, developed by De Ryck et al16 to examine sensorimotor integration in forelimb placing responses to visual, tactile, and proprioceptive stimuli. Neurological function (Table 1
) was graded on a scale of 0 to 12 (normal score, 0; maximal score, 12). Rats with convulsions or sustained disturbances of consciousness were excluded from the study; most of these cases proved to have subarachnoid hemorrhage secondary to suture-induced rupture of the ICA. In the present study only one animal from the 60-minute uncoated group was excluded for the above reason.
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Infarct Assessment
Animals were allowed to survive for 3 days. Brains were then perfusion-fixed as previously described17 with a mixture of 40% formaldehyde, glacial acetic acid, and methanol (FAM, 1:1:8 by volume), and brain blocks were embedded in paraffin. Ten-micrometer-thick sections were cut in the coronal plane and stained with hematoxylin and eosin. To quantitate infarct volume and depict infarct frequency distribution, coronal sections were viewed microscopically at low power, and the areas of infarction at nine coronal levels throughout the brain were traced and measured with the aid of a camera lucida microscope attachment.18 19 These drawings of infarcted zones were then video-digitized and saved as digital images. A value of 1 was assigned to each pixel inside an infarcted region, and the remaining pixels were assigned a value of 0. We then mapped corresponding sections into a preselected "template" section derived from one of the animals studied. This mapping procedure was based on a well-validated image matching/registration algorithm termed "disparity analysis."20 Pixel-based summation of these mapped digital histological drawings resulted in frequency maps showing, for each image pixel, the number of animals with infarction. Computational procedures were performed on a MicroVAX 3600 computer (32 megabytes of RAM), and image display and analysis were performed on a VAX Station 3200 (8-bit color plane, 16 megabytes of RAM) (Digital Equipment Corp). The volume of infarction was calculated as the product of cross-sectional area for all sections and distance between sections, by an investigator who was blinded to the experimental groups. To compensate for brain swelling in the ischemic hemisphere,21 we corrected infarct volume in each rat by computing the volume of the left and right hemispheres and applying the following formula: Corrected Infarct Volume=Left Hemisphere Volume-(Right Hemisphere Volume-Measured Infarct Volume).
Statistical Analysis
Infarct areas were analyzed by repeated measures ANOVA and by post hoc Bonferroni testing, which accounted for multiple comparisons. Total infarct volumes and physiological variables were compared by Student's t test. Fisher's exact test was used to compare the frequency of infarction between groups, and the Spearman ordinal rank test was used to relate neurological scores and infarct volumes. P<.05 was regarded as significant. Values are presented as mean±SEM.
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Results |
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Rectal and cranial (temporalis muscle) temperatures, mean arterial blood pressure, plasma glucose, and blood gases in the 23 animals of this study showed no significant differences between groups (Table 2
). Neurological deficits were observed to be maximal at 50 or 60 minutes in all rats (Fig 1). Contralateral forelimb placing deficits were clearly present at 50 minutes after 60 minutes of MCAo, and there was a trend toward better recovery in uncoated than in poly-L-lysine-coated groups, but this difference was not statistically significant. The neurological scores after 2 hours of MCAo were significantly worse in the group with poly-L-lysine-coated sutures than in rats with uncoated sutures at 60 minutes and at 24 and 48 hours (9.0±0 versus 8.3±0.2, 8.8±0.3 versus 7.3±0.5, and 8.5±0.3 versus 6.0±0.6, respectively).
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Histological examination of the brains of both groups after 72-hour survival showed a consistent pattern of ischemic brain damage, characterized by a mixture of infarction and selective ischemic neuronal changes.22 In the 60-minute MCAo study, ischemic changes were restricted to the caudoputamen. In rats with uncoated sutures, these infarcts were smaller and tended to be variable and inconsistent (Fig 2A); only 3 of 7 animals showed histological infarcts. In contrast, all animals of the 60-minute poly-L-lysine-coated group (n=7) had infarcts localized to the lateral segment and, to a varying extent, the medial segment of the caudate nucleus (Fig 2B). This intergroup difference in the frequency of infarction was highly significant (P=.009, Fisher's exact test).
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The areas of infarction included pancellular necrosis as well as dense areas of eosinophilic, shrunken neurons along the edges of the infarct. After 60 minutes of MCAo, there was a tendency for total infarct volume to be greater in the poly-L-lysine-coated group than in the group with uncoated sutures (48.1±6.9 versus 29.8±19.9 mm3, respectively; n=7 in each group), but this difference was not statistically significant. Nonetheless, the coefficient of variation of infarct volume was dramatically smaller in the former than in the latter group (38% versus 177%, respectively). Fig 3 illustrates the rostrocaudal distribution of infarct areas in the two groups standardized according to the atlas of Konig and Klippel.23 Infarct areas were significantly larger in the group with poly-L-lysine-coated sutures than in the uncoated-suture group at coronal levels 3 (bregma +1.2 mm) and 5 (bregma -1.3 mm).
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In the 2-hour MCAo study, infarcts of the caudoputamen were smaller in the uncoated-suture group (n=4), and cortical infarct volumes tended to be variable and inconsistent (Fig 2C
). In contrast, all 2-hour MCAo rats with poly-L-lysine-coated sutures (n=4) showed infarcts of the caudoputamen, and the frontoparietal somatosensory cortex was consistently infarcted (Fig 2D). Total infarct volume was significantly larger in the group with poly-L-lysine-coated sutures than in the uncoated-suture group (122.1±4.8 mm3 and 66.95±18.2 mm3, respectively; Fig 4A), and the coefficient of variation was reduced by more than 85% (8% versus 54%, respectively). Fig 4B and 4C illustrates the rostrocaudal distribution of infarct areas in cortical and subcortical regions. Infarct areas were significantly larger in the group with poly-L-lysine-coated sutures than in the uncoated-suture group at coronal levels 2 (bregma +2.7 mm) and 8 (bregma -5.0 mm) for the cortex, and at coronal levels 4 (bregma -0.3 mm) and 5 (bregma -1.3 mm) for the caudoputamen. Mortality during the 3 days after MCAo was confined to the uncoated-suture group: 1 rat in the 60-minute MCAo study and 2 rats in the 2-hour MCAo study.
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Fig 5 presents digitized frequency maps comparing the distribution of infarction in rats with coated versus uncoated sutures and with 60 minutes versus 2 hours of MCAo. Fisher's exact tests performed on a pixel-by-pixel basis revealed that the use of coated sutures greatly increased the consistency of infarction in both the 60-minute (Fig 5C) and the 2-hour (Fig 5F) MCAo groups. Figs 5G and 5H confirm that extending the duration of MCAo from 60 minutes to 2 hours leads to a recruitment of neocortex into the ischemic lesion in both the uncoated- and the coated-suture groups, with cortical involvement consistently greater in the 2-hour MCAo group with coated sutures (Fig 5H).
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In pooled rats with 2-hour MCAo (n=8), the Spearman rank correlation test was used to assess the relationship between total neurological score at 72 hours and infarct volume. A significant ordinal correlation was noted between neurological score and caudoputaminal infarct volume (P=.015) but not cortical infarct volume.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Animal models of focal cerebral ischemia in which MCAo is used reproduce the pattern of ischemic brain damage observed in many human ischemic stroke patients.2 3 Depending on the model, ischemia may extend throughout the vascular territory of the MCA15 and give rise to focal metabolic disturbances that result in infarction, selective neuronal necrosis, and brain edema.24 25 Techniques for inducing transient MCAo by an intraluminal filament have been extensively used in experimental models of ischemic stroke.9 26 27 These methods have the advantage of not requiring craniotomy with its associated operative trauma, and they permit reperfusion of the occluded MCA. Koizumi et al9 used a silicone-coated 4-0 nylon surgical thread (diameter, 0.25 to 0.30 mm), while Zea Longa et al10 used a 4-0 uncoated nylon thread whose tip was blunted by heating near a flame. Both groups showed that reperfusion occurred when the threads were removed. As discussed by Laing et al,28 the method of Zea Longa et al10 has relatively low reproducibility, with the success rate in achieving infarction only 56% compared with 93% in the model of Koizumi et al.9 In another study in which a silicone-coated thread was used, approximately 30% of experimental animals had to be excluded.29 Unsuccessful outcomes consisted of animals without neurological deficits and rats in which subarachnoid hemorrhage caused by rupture of the intracranial ICA had occurred. In the study of Nagasawa and Kogure,26 in which the MCA was occluded with a silicone rubber cylinder attached to a nylon surgical thread, 38 of 41 rats died within 48 hours after MCAo; the overall mortality rate was 92.7%.
In our own preliminary experiments in which uncoated sutures were used, the success rate was also rather low. Thus, we adopted the method of Zea Longa et al10 while modifying the technique of suture preparation: we blunted the tip of the thread and then coated it with poly-L-lysine.11 Poly-L-lysine has previously been shown to promote the adherence of cells and proteins to glass and plastic surfaces.13 Successful MCAo was achieved in all 11 animals of the two MCAo groups in which a coated suture was used. In this ischemic model, all rats with coated sutures showed consistent damage to the lateral and medial segments of the caudoputamen at 72 hours after 60-minute MCAo, while only 3 of 7 rats with uncoated sutures showed infarcts of the caudoputamen. With longer periods of proximal MCAo, infarcts are typically composed of two zones: cortical and subcortical.30 In the present 2-hour MCAo study, infarct involving cortical and subcortical regions of the right MCA territory was present in all rats in which sutures were coated with poly-L-lysine, and the mean increase in infarct volume over rats with uncoated sutures was 182%.
Observation of neurological deficits is important not only in clinical stroke patients but also in animal models of cerebral ischemia. The advent of novel medical therapies to protect the ischemic brain has heightened the need to relate the severity and duration of neurological deficits after experimental cerebral ischemia to the duration and intensity of the antecedent insult and, in particular, to ascertain the effects of reperfusion.31 32 However, it is sometimes difficult to detect neurological deficits after cerebral ischemia in rodents. In the present study of reversible MCAo, we used a standardized quantitative neurobehavioral battery to compare the initial severity and subsequent recovery of neurological function in rats with versus without poly-L-lysine–coated sutures. Focal ischemia induced a neurological deficit characterized by sensorimotor dysfunction, as has been noted by previous workers.15 33 34 Two tests of the sensorimotor battery appeared to be particularly sensitive in detecting deficits after MCAo: the postural reflex test and the forelimb placing test. In rats with 2-hour MCAo, there was a significant positive ordinal relationship between total neurological score at 72 hours and the volume of the infarcted caudoputamen. Those rats with poly-L-lysine–coated sutures not only exhibited larger infarcts but were also more severely impaired on neurobehavioral tests than the uncoated-suture group and showed a slower recovery of function (Fig 1). While Wahl et al35 reported a lack of correlation between neurological deficit and the extent of the infarct, others have shown that the neurological deficit correlated significantly with the size of the infarcted area.15 36 In a recent study from our laboratory in which permanent distal photothrombotic MCAo was used, the cumulative neurobehavioral index correlated positively with the volume of total ischemic injury.37
In the present study, the pattern of behavioral deficit and subsequent recovery after 60 minutes of MCAo was less homogeneous than after 2 hours of MCAo. These differences between the 60-minute and 2-hour MCAo groups may be due to the fact that after 60 minutes of MCAo, only the striatum is consistently damaged, whereas after 2 hours of MCAo the infarct typically involves both the striatum and frontoparietal cortex.
Complete physiological monitoring, including attention to body and brain temperatures, plasma glucose level, arterial blood pressure, and blood gases, is required to ensure an interpretable outcome in this and other models of ischemia.
Major advantages of the improved intraluminal MCAo model reported here, incorporating sutures coated with poly-L-lysine, include a 100% incidence of infarction after both 60 minutes and 2 hours of MCAo; the predictable location and size of the infarct, with high interanimal reproducibility (low coefficient of variation); and the consistent production of neurological deficits. Because the model is reproducible, the effects of various therapeutic agents on neurological outcome and size of infarction produced by focal cerebral ischemia can be studied.11
In summary, we have shown that the suture model of MCAo, as modified and improved in our laboratory, provides a useful means of studying reversible focal cerebral ischemia.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by US Public Health Service grant 05820. The authors thank Susan Kraydieh for technical assistance, Helen Valkowitz for typing the manuscript, and Drs W. Dalton Dietrich and Ricardo Prado for their assistance and advice.
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Footnotes |
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Reprint requests to Myron D. Ginsberg, MD, Department of Neurology (D4-5), University of Miami School of Medicine, PO Box 016960, Miami, FL 33101.
Received February 6, 1996; revision received April 22, 1996; accepted May 16, 1996.
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Editorial Comment
Neurological and Pathological Evaluation of an Improved Model
Cerebrovascular Disease SectionDepartment of NeurologyWashington University School of MedicineSt. Louis, Mo
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Animal stroke models have been used extensively in studying the pathophysiology of cerebral ischemia and in screening novel neuroprotective agents that may be applied to treat patients with stroke. For social, economic, and methodological reasons, rodents, especially rats, have become the major species adapted by stroke researchers in the development of animal stroke models. The advantages of using rats include the similarity of their brain anatomy to the human brain and close proximity of the neurotransmitter system between the two species. MCAo in rats has been achieved by a number of methods.1R 2R 3R These methods produce consistently large infarct volumes in well-defined MCA territory. The major drawbacks of these methods are (1) the need to create a craniotomy; (2) the necessity of sacrificing the MCA by cauterization1R 2R or permanent ligation3R ; (3) the demand of a skillful animal surgeon experienced in microsurgery; and (4) lack of an option for full reperfusion of the MCA. While later models of MCAo feature reversible MCAo in which the ligature is tied and subsequently untied, permitting full reperfusion of the MCA,4R the delicate surgical procedure poses an even greater technical challenge.
In the accompanying article, Belayev et al have described the advantages of a "suture" model of MCAo that was pioneered by Koizumi et al5R and refined by Zea Longa and coworkers.6R The suture models have gained increasing popularity in recent years and have been modified to conduct sophisticated pathophysiological studies such as diffusion-weighted MRI.7R 8R A suture model has been introduced in mice in transgene experiments.9R 10R A major disadvantage of the suture models is inconsistency in infarct development, with the exception of aged rats.11R Belayev and coworkers, by coating the suture with poly-L-lysine, have shown substantial improvement in consistency in infarct size. This is an encouraging development that addresses a major shortcoming of the suture model. Wider application of this method is needed to further define its advantage in infarct creation and to determine whether the following problems inherent to the suture models can be overcome with this modified method: (1) death; (2) failure to advance the catheter to the desirable intracranial location; and (3) subarachnoid hemorrhage.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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1R. Tamura A, Graham DI, McCulloch J, Teasdale GM. Focal cerebral ischemia in the rat: description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1981;1:53-60.
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3R. Brint S, Jacewicz M, Kiessling M, Tanabe J, Pulsinelli W. Focal brain ischemia in the rat: methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries. J Cereb Blood Flow Metab. 1988;8:474-485.[Medline] [Order article via Infotrieve]
4R. He YY, Hsu CY, Ezrin AM, Miller MS. Polyethylene glycol conjugated superoxide dismutase in focal cerebral ischemia-reperfusion. Am J Physiol. 1993;265(Heart Circ Physiol 34):H252-H256.
5R. Koizumi J, Yoshida Y, Nazakawa T, Ooneda G. Experimental studies of ischemic brain edema, I: a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke.. 1986;8:1-8.
6R. Zea Longa EL, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20:84-91.
7R. Minematsu K, Fisher M, Li L, Sotak CH. Diffusion and perfusion magnetic resonance imaging studies to evaluate a noncompetitive N-methyl-D-aspartate antagonist and reperfusion in experimental stroke in rats. Stroke. 1993;24:2074-2081.
8R. Hoehn-Berlage M, Norris DG, Kohno K, Mies G, Leibfritz D, Hossmann KA. Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances. J Cereb Blood Flow Metab.. 1995;15:1002-1011.[Medline] [Order article via Infotrieve]
9R. Yang G, Chan PH, Chen J, Carlson E, Chen SF, Weinstein P, Epstein CJ, Kamii H. Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke. 1994;25:165-170.
10R. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994;265:1883-1885.
11R. Wang LC, Futrell N, Wang DZ, Chen FJ, Zhai QH, Schultz LR. A reproducible model of middle cerebral infarcts, compatible with long-term survival, in aged rats. Stroke. 1995;26:2087-2090.
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