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Logo of extranstromedBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleExperimental & Translational Stroke MedicineJournal Front Page
Exp Transl Stroke Med. 2009; 1: 7.
Published online Nov 13, 2009. doi:  10.1186/2040-7378-1-7
PMCID: PMC2820445

Animal models of focal brain ischemia

Abstract

Stroke is a leading cause of disability and death in many countries. Understanding the pathophysiology of ischemic injury and developing therapies is an important endeavor that requires much additional research. Animal stroke models provide an important mechanism for these activities. A large number of stroke models have been developed and are currently used in laboratories around the world. These models are overviewed as are approaches for measuring infarct size and functional outcome.

Utility of Animal Models of Ischemic Stroke

Stroke is the third leading cause of death and a major cause of disability in the United States [1,2]. Each year, there are approximately 731,000 new strokes and half of the survivors suffer from permanent handicap [3]. Stroke costs the United States approximately $50 billion annually in direct and indirect costs [4]. Given these facts, stroke is a major public health issue requiring urgent development of effective therapies: experimental models of focal brain ischemia help in achieving this goal.

80% of human strokes are ischemic in origin [2]. Thus, experimental models of focal cerebral ischemia have been developed in an attempt to closely mimic the changes that occur during and after human ischemic stroke. These models are used to discover the mechanisms involved in the evolution of ischemic injury which, in turn, can lead to the development of novel therapeutic strategies for stroke. These same animal models can then be used to test the safety and efficacy of these treatments in vivo.

Most human ischemic strokes are caused by occlusion of the middle cerebral artery (MCA) [5] and so animal models were developed to induce ischemia in this arterial territory. These models aim to satisfy the following criteria: (1) to mimic the pathophysiological changes found in human stroke, (2) to create reproducible lesions, (3) to employ procedures that are relatively simple and noninvasive, (4) to be of low financial cost, and (5) to enable monitoring of physiologic parameters and analysis of brain tissue for outcome measures [6].

Many higher animal species fulfill the aforementioned stroke modeling criteria; however, rats are the most commonly used animals for several reasons, including: (1) their resemblance to humans in their cerebral anatomy and physiology, (2) their small size which enables easy analysis of physiology and brain tissue, (3) their low cost, (4) the remarkable genetic homogeneity within strains, and (5) greater public and institutional ethical acceptability of use relative to larger animals. Thus, the remainder of this chapter will focus primarily on rat models of ischemic stroke [7-9].

Permanent versus Transient Ischemia

Focal brain ischemia models can be categorized into two groups: permanent and transient ischemia. Permanent ischemia results in a region of severe ischemic damage (core) surrounded by a zone of less damaged tissue [10]. Reestablishment of perfusion after 3 hours does not reduce infarct size in all animal models [11].

Transient focal ischemia produces varying degrees of ischemic damage depending on the duration of ischemia. In rats, as little as 8 minutes of ischemia causes selective neural necrosis and ischemia for more than 30 minutes is always associated with infarction [12]. Importantly, after transient ischemia, brain damage results from both the ischemia and the effects of reperfusion (reperfusion injury). Compared to permanent occlusion, which mimic only a minority of human strokes where there is no recanalization, transient models better correlate with conditions such as therapy-induced thrombolysis, spontaneous thrombolysis, and transient ischemic attack. However, both permanent and transient ischemia models are needed prior to clinical drug development studies because of the heterogeneity of human stroke [13,14].

Long-term studies are becoming increasingly important in translational stroke research; thus, the animal survival rate should be considered when designing an experimental protocol. Generally, regardless of the employed technique, models of transient ischemia offer higher survival rates relative to permanent occlusion and thus may be more suited for long-term studies. Additionally, survival is enhanced by proper surgical technique, maintaining physiological parameters within normal ranges during experimentation, and attention to animal nutrition, among other things. For studies of neuroprotection and/or thrombolysis, the effects of putative therapies on survivability must also be taken into consideration.

Rat Models of Focal Cerebral Ischemia

Many animal models of focal cerebral ischemia exist. In this chapter, special focus is paid to the intraluminal MCA occlusion and embolus models because of their relatively widespread use in the development of treatments for stroke. Importantly, these methods can also be performed on mice, allowing for transgenic studies of the pathophysiology of stroke.

Intraluminal MCA Occlusion Model

This model was originally described by Koizumi et al and has since been modified by others [11]. It is the most commonly used of rat models of stroke due to its relative simplicity and noninvasiveness. The MCA is occluded by inserting a monofilament suture into the internal carotid artery (ICA) to block blood flow to the MCA either permanently or transiently by keeping the filament in place or withdrawing it, respectively. Several manuscripts describe in detail the technical and procedural features of this model [11-16].

This model typically induces infarcts in the lateral caudatoputamen and frontoparietal cortex [17]. The infarct is reproducible and there is a significant ischemic penumbra early after MCA occlusion, making this model suitable for testing neuroprotective agents [18]. However, several technical factors may influence infarct size, such as: 1) physical differences in the employed monofilament suture, (2) insertion distance of the suture, and (3) accidental premature reperfusion [19-21]. It is therefore essential that standardized surgical and technical procedures be used by adequately trained personnel in order to generate reproducible lesions. There are also some complications with the intraluminal MCA occlusion model such as subarachnoid hemorrhage secondary to suture-induced arterial rupture, spontaneous hyperthermia when the duration of ischemia is longer than 2 h, and mechanical damage of endothelium which can complicate reperfusion [13,22,23]. The complication rates may be reduced by using silicone coated sutures [13].

The intraluminal MCAO model is suitable for neuroprotection drug experiments because it produces a substantial amount of penumbra (salvageable tissue) in the first 60-90 minutes after onset [16]. Also, the location, volume, and temporal evolution of infarction are similar to those produced by proximal electrocoagulation of the MCA [16]. The suture is easily withdrawn, enabling investigators to study the aspects of reperfusion

The suture MCA occlusion model has recently been modified to induce ischemia in a magnetic resonance imaging (MRI) unit by remotely advancing the suture occluder [16]. This in-bore occlusion method has achieved a high reproducibility rate and enables investigators to monitor in vivo ischemic changes at pre-occlusion, acute, subacute and chronic post-occlusion time points [16]. Combined with multiparametric MRI techniques, the MCA occlusion model enables anatomic, diffusion, perfusion, and functional data to be obtained longitudinally and noninvasively in the same animal, making it a powerful tool for studying the pathophysiology of brain ischemia [23,24].

Thromboembolic Model

Though thromboembolic ischemia can be induced by a photochemical approach, the most commonly used thromboembolic model is blood clot injection, first described in the dog by Hill et al. and later applied to the rat [25-27]. This model is of great interest to researchers because of its close resemblance to human ischemic stroke and its utility in evaluating thrombolytic therapies [28]. Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) administered intravenously within 3 h of onset of ischemic stroke in select patients is the only FDA-approved treatment for human stroke and has been shown to improve neurological outcome [29]. Recently, there has been heightened interest in studying the efficacy of combining thrombolytic and neuroprotective agents in the treatment of stroke, giving thromboembolic animal models an increasingly important role in this respect [30].

Several disadvantages were common to the early thromboembolic models, such as diffuse and inhomogenous infarction in the MCA territory from microembolization to peripheral branches [27]. Additionally, spontaneous recanalization frequently occurred, making it difficult to study thrombolytic therapies [16]. Infarct sizes were variable, contralateral strokes were common, and ischemia caused by multiple small clots did not mimic typical clinical ischemic stroke [16]. Later, it was determined that size (length and diameter) and the biological characteristics of the blood clot (fibrin-rich) are crucial to the relevance and reproducibility of this model [16].

Busch et al developed a rat clot model that surmounted the above issues in which a single fibrin-rich autologous clot was injected to produce reliable occlusion of the proximal MCA, with consistent reduction of cerebral blood flow (CBF) and histological damage in the MCA territory seen [31]. No spontaneous thrombolysis was observed and, in separate experiments, thrombolytic therapy with rt-PA or prourokinase recanalized the occluded MCA [31,32]. Recently, Henninger et al used the embolic model in conjunction with multimodal MRI to investigate the pathophysiological mechanisms underlying the relatively rare clinical phenomenon of "spectacular shrinking deficit" in stroke patients [33].

In conclusion, the single fibrin-rich clot model induces reproducible infarcts in the MCA territory similar to those produced by the intraluminal MCA occlusion model. The clot model has the added advantages of bearing closer similarity to the mechanism underlying human ischemic stroke and better utility for studying thrombolytic therapy. Combined with modern imaging techniques, thromboembolic models have the potential to take the experimental study of stroke to new frontiers.

Non-clot Embolus Models

Numerous compounds have been used to produce artificial emboli which are typically injected into the ICA, most commonly in rats [34]. Microsphere embolization is the most widely used model, with the severity of ischemic damage related to the number of emboli used [35]. The lesions require longer time to develop (24 hours on average) than in the intraluminal models, allowing for a larger therapeutic window for drug testing in microsphere models. However, the permanency of the ischemia does not simulate most clinical situations which limits the applicability of these models. Also, lesions are multifocal and have low reproducibility, though recent macrosphere models have resulted in more reproducible infarcts by increasing the diameter of the spheres and using less of them [36].

Direct Surgical MCAO

Numerous techniques have been developed to surgically approach and occlude the MCA, with the rat being the species most widely used [13]. The orbital route is the least traumatic and, compared to procedures requiring craniotomy, results in less blood loss and artifacts [37]. Electrocautarization of the MCA results in permanent occlusion, whereas clipping or ligature snares enable reperfusion [38]. Occlusion of the MCA following a transient hypotension produces a larger infarct area [39]. Tandem occlusion of the distal MCA and ipsilateral CCA results in more reproducible infarcts [40]. Recently, a three-vessel occlusion model has been shown to produce reproducible and selective neocortical infarction [41]. Common to all of these variants, the procedure is always invasive and requires extreme surgical skill which limits their utility.

Photochemically Induced Thrombosis

This model induces a cortical infarct by systemic injection of a photoactive dye in combination with irradiation by a light beam transmitted through the intact skull [42]. Oxidative damage to the endothelium caused by the altered dye leads to platelet aggregation in the irradiated area [43]. This model is used primarily in spontaneously hypertensive rats [44]. A disadvantage of this model is that vasogenic edema and blood-brain barrier breakdown occur within minutes which does not allow for the formation of penumbra--therefore, this model has been considered by many to be unsuitable for preclinical drug studies [44]. However, a new model overcomes this limitation and induces ischemia over a greatly extended time period, consistently producing a penumbra-like region [45]. This, combined with the ability to noninvasively and reproducibly induce infarct in any cortical location, are obvious advantages of the photochemical infarct model. A major disadvantage is the atypical features of the lesion (prominent vascular injury and early vasogenic edema) which are unlike human stroke [13].

Endothelin-induced MCAO

Endothelin-1 (ET-1) is a natural peptide that causes vasoconstriction and several models use this as an agent to induce MCA stroke [13]. Invasive approaches have been largely replaced by stereotactic intracerebral injection of ET-1 adjacent to the MCA, which avoid complications of surgery [46]. When ET-1 is applied to the MCA there is a significant decrease of cerebral blood flow (CBF) in its territory, resulting in an ischemic lesion pattern similar to that of direct surgical MCAO [47]. This model may be useful in restorative drug studies. Notably, after a period (~20 minutes) of severe CBF reduction, there is a slow and progressive return of blood flow to normal with the rate being dose-dependent [47]. This can be disadvantageous source of variability unless the dose is carefully standardized in the experiment.

Outcome Measures

There are several ways of measuring the severity of ischemic insult in animals: assessment of neurological status, pathological assessment, and in-vivo evaluation with magnetic resonance imaging (MRI). Most prior studies of MCAO focus on the acute phase of ischemia but since neuronal damage can occur days to weeks after insult, it is reasonable that new studies include evaluation of outcome measures both in the acute phase (1-3 days) and chronically (up to 4 weeks) [48].

Assessment of Neurological Status

Many neurological deficits are difficult to assess in animals. Motor deficits are perhaps the easiest to quantify and simple measures of motor function are available in rodent models [49]. Refined tests that assess sensorimotor function include limb placing, beam walking, sticky label test, grid walking, and rotarod [50]. A number of cognitive tests examining learning and short term memory are available for rats, including the Morris water maze [51]. Combining neurological assessment with histological measurements is becoming more critical with the heightened interest in neuroprotective drugs, the effectiveness of which may be reflected more by subtle structural and chemical changes rather than changes in gross infarct volume [52]. This statement is supported by the fact that animal data suggest a poor correlation between reductions in infarct size with neurological or behavioral deficits [13]. Also of importance is the need to extend the period of testing of neurological status for at least 1 month post-insult in animal studies, per the recommendations of the STAIR Committee [14]. However, this may be difficult to implement as survival times are 48 hours or less in many animal stroke models [53].

Pathological Assessment

In models of focal ischemia, the chief outcome has been the infarct volume, traditionally measured by quantitative histology. Among a number of histopathological methods, 2,3,5-triphenyltetrazolium chloride (TTC) and hematoxylin-eosin (H&E) staining are the two most commonly employed. TTC can be used to stain tissue much more rapidly, easily, and cheaply than H&E [54]. TTC is a colorless chemical that is reduced by mitochondrial enzymes into a compound that stains intact brain regions dark red whereas infarcted regions remain white. Studies show TTC staining to be reliable between 6 and 72 hours post-ischemia [13]. Prior to 6 hours, there may not be sufficient number of damaged mitochondria to create contrast between normal and infarcted tissue, and after 72 hours pathophysiologic inflammatory response often obscures the line of demarcation in the periphery of the damaged area [13].

Notwithstanding staining techniques, infarcts have complex shapes with sometimes indistinct margins, making it difficult to measure their volumes. Many methods have been developed to deal with these complexities, each with their own advantages and disadvantages. Perhaps one of the most important considerations to account for is the effect of vasogenic edema on infarct volume. Edema in the rat MCAO stroke model typically accounts for 20-30% of the total apparent infarct volume [55]. Separate measurement of "corrected" infarct volume (which accounts for edema) and "uncorrected" volume (which does not account for edema) is important because of the possibility that some interventions may reduce edema but not salvage brain tissue and vice-versa [13].

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

Both KMS and MF performed background research and wrote the manuscript. All authors read and approved the final manuscript.

References

  • Bonita R. In: Stroke Prevention. Norris JW, Hachinksi V, editor. New York: Oxford University Press; 2001. Stroke prevention: global perspective; pp. 259–274.
  • Sacco RL, Wolf PA, Gorelick PB. Risk factors and their management for stroke prevention: outlook for 1999 and beyond. Neurology. 1999;53:S15–S24. [PubMed]
  • Kaste M, Fogelholm R, Rissanen A. Economic burden of stroke and the evaluation of new therapies. Public Health. 1998;112:103–112. [PubMed]
  • Sacco RL, Boden-Albala B. In: Stroke Therapy. 2. Fisher M, editor. Woburn, MA: Butterworth-Heinemann; 2001. Stroke risk factors: identification and modification; pp. 1–24.
  • del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, Alberts MJ, Zivin JA, Wechsler L, Busse O. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992;32:78–86. doi: 10.1002/ana.410320113. [PubMed] [Cross Ref]
  • Hsu CY. Criteria for valid preclinical trials using animal stroke models. Stroke. 1993;24:633–636. [PubMed]
  • Yamori Y, Horie R, Handa H, Sato M, Fukase M. Pathogenetic similarity of strokes in stroke-prone spontaneously hypertensive rats and humans. Stroke. 1976;7:46–53. [PubMed]
  • Coyle P. Middle cerebral artery occlusion in the young rat. Stroke. 1982;13:855–859. [PubMed]
  • Ginsberg MD, Busto R. Rodent models of cerebral ischemia. Stroke. 1989;20:1627–1642. [PubMed]
  • Hunter AJ, Green AR, Cross AJ. Animal models of acute ischaemic stroke: can they predict clinically successful neuroprotective drugs? Trends Pharmacol Sci. 1995;16:123–128. doi: 10.1016/S0165-6147(00)88999-3. [PubMed] [Cross Ref]
  • Grotta J. In: Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Ginsberg MD, Bogousslavsky J, editor. Blackwell Scientific, Malden, MA; 1998. Stroke treatment in the human versus animal models.
  • Li F, Han SS, Tatlisumak T, Liu KF, Garcia JH, Sotak CH, Fisher M. Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats. Ann Neurol. 1999;46:333–342. doi: 10.1002/1531-8249(199909)46:3<333::AID-ANA9>3.0.CO;2-X. [PubMed] [Cross Ref]
  • Durukan A, Tatlisumak T. In: Handbook of Clinical Neurology., (3rd series), Stroke, Part 1 Basic and epidemiological aspects. Fisher M, editor. Vol. 92. New York. Elsevier; 2009. Animal models of ischemic stroke; pp. 1–464.
  • Fisher M. Recommendations for advancing development of acute stroke therapies: Stroke Therapy Academic Industry Roundtable 3. Stroke. 2003;34:1539–1546. doi: 10.1161/01.STR.0000072983.64326.53. [PubMed] [Cross Ref]
  • Li F, Han S, Tatlisumak T, Carano RA, Irie K, Sotak CH, Fisher M. A new method to improve in-bore middle cerebral artery occlusion in rats: demonstration with diffusion- and perfusion-weighted imaging. Stroke. 1998;29:1715–1720. [PubMed]
  • Li F, Tatlisumak T. In: Handbook of Experimental Neurology: Methods and Techniques in Animal Research. Tatlisumak, Fisher M, editor. Cambridge: Cambridge University Press; 2006. Focal brain ischemia models in rodents; pp. 311–328.
  • Meng X, Fisher M, Shen Q, Sotak CH, Duong TQ. Characterizing the diffusion/perfusion mismatch in experimental focal cerebral ischemia. Ann Neurol. 2004;55:207–212. doi: 10.1002/ana.10803. [PMC free article] [PubMed] [Cross Ref]
  • Kuge Y, Minematsu K, Yamaguchi T, Miyake Y. Nylon monofilament for intraluminal middle cerebral occlusion in rats. Stroke. 1995;26:1655–1658. [PubMed]
  • Zarow GJ, Karibe H, States BA, Graham SH, Weinstein PR. Endovascular suture occlusion of the middle cerebral artery in rats: effect of suture insertion distance on cerebral blood flow, infarct distribution and infarct volume. Neurol Res. 1997;19:409–416. [PubMed]
  • Schmid-Elsaesser R, Zausinger S, Hungerhuber E, Baethmann A, Reulen HJ. A critical reevaluation of the intraluminal thread model of focal cerebral ischemia: evidence of inadvertent premature reperfusion and subarachnoid hemorrhage in rats by laser-Doppler flowmetry. Stroke. 1998;29:2162–2170. [PubMed]
  • Zhao Q, Memezawa H, Smith ML, Siesjo BK. Hyperthermia complicates middle cerebral artery occlusion induced by an intraluminal filament. Brain Res. 1994;649:253–259. doi: 10.1016/0006-8993(94)91071-5. [PubMed] [Cross Ref]
  • Li F, Omae T, Fisher M. Spontaneous hyperthermia and its mechanism in the intraluminal suture middle cerebral artery occlusion model of rats. Stroke. 1999;30:2464–2471. [PubMed]
  • Sicard KM, Henninger N, Fisher M, Duong TQ, Ferris CF. Differential recovery of multimodal MRI and behavior after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2006;11:1451–1462. doi: 10.1038/sj.jcbfm.9600299. [PMC free article] [PubMed] [Cross Ref]
  • Sicard KM, Henninger N, Fisher M, Duong TQ, Ferris CF. Long-term changes of functional MRI-based brain function, behavioral status, and histopathology after transient focal cerebral ischemia in rats. Stroke. 2006;10:2593–2600. doi: 10.1161/01.STR.0000239667.15532.c1. [PMC free article] [PubMed] [Cross Ref]
  • Hill NC, Millikan CH, Wakim KG, Sayre GP. Studies in cerebrovascular disease. VII. Experimental production of cerebral infarction by intracarotid injection of homologous blood clot: preliminary report. Mayo Clin Proc. 1955;30:625–633. [PubMed]
  • Futrell N, Watson BD, Dietrich WD, Prado R, Millikan C, Ginsberg MD. A new model of embolic stroke produced by photochemical injury to the carotid artery in the rat. Ann Neurol. 1988;23:251–257. doi: 10.1002/ana.410230307. [PubMed] [Cross Ref]
  • Kudo M, Aoyama A, Ichimori S, Fukunaga N. An animal model of cerebral infarction: homologous blood clot emboli in rats. Stroke. 1982;13:505–508. [PubMed]
  • Albers GW. Antithrombotic agents in cerebral ischemia. Am J Cardiol. 1995;75:348–388. doi: 10.1016/0002-9149(95)80008-G. [PubMed] [Cross Ref]
  • National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group T. Tissue plasminogen activator for acute ischemic stroke. New Engl J Med. 1995;333:1581–1587. doi: 10.1056/NEJM199512143332401. [PubMed] [Cross Ref]
  • Savitz SI, Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann Neurol. 2007;5:396–402. doi: 10.1002/ana.21127. [PubMed] [Cross Ref]
  • Busch E, Kruger K, Hossmann KA. Improved model of thromboembolic stroke and rt-PA induced reperfusion in the rat. Brain Res. 1997;778:16–24. doi: 10.1016/S0006-8993(97)01008-1. [PubMed] [Cross Ref]
  • Takano K, Carano RA, Tatlisumak T, Meiler M, Sotak CH, Kleinert HD, Fisher M. Efficacy of intra-arterial and intravenous prourokinase in an embolic stroke model evaluated by diffusion-perfusion magnetic resonance imaging. Neurology. 1998;50:870–875. [PubMed]
  • Henninger N, Sicard KM, Fisher M. Spectacular shrinking deficit: insights from multimodal magnetic resonance imaging after embolic middle cerebral artery occlusion in Sprague-Dawley rats. J Cereb Blood Flow Metab. 2007;10:1756–1763. doi: 10.1038/sj.jcbfm.9600477. [PubMed] [Cross Ref]
  • Molnar L, Hegedus K, Fekete I. A new model for inducing transient cerebral ischemia and subsequent reperfusion in rabbits without craniectomy. Stroke. 1988;19:1262–1266. [PubMed]
  • Zivin JA, DeGirolami U, Kochhar A, Lyden PD, Mazzarella V, Hemenway CC, Henry ME. A model for quantitative evaluation of embolic stroke therapy. Brain Res. 1987;435:305–309. doi: 10.1016/0006-8993(87)91613-1. [PubMed] [Cross Ref]
  • Gerriets T, Li F, Silva MD, Meng X, Brevard M, Sotak CH, Fisher M. The macrosphere model: evaluation of a new stroke model for permanent middle cerebral artery occlusion in rats. J Neurosci Methods. 2003;122:210–211. doi: 10.1016/S0165-0270(02)00322-9. [PubMed] [Cross Ref]
  • Pulsinelli W, Jacewicz M. In: Stroke: Pathophysiology, Diagnosis, and Management. 2. Barnett HJ, Mohr JP, Stein BM, et al, editor. Churchill Livingstone, New York; 1992. Animal models of brain ischemia.
  • Shigeno T, Teasdale GM, McCulloch J, Graham DI. Recirculation model following MCA occlusion in rats. Cerebral blood flow, cerebrovascular permeability, and brain edema. J Neurosurg. 1985;63:272–277. doi: 10.3171/jns.1985.63.2.0272. [PubMed] [Cross Ref]
  • Osborne KA, Shigeno T, Balarsky AM, Ford I, McCulloch J, Teasdale GM, Graham DI. Quantitative assessment of early brain damage in a rat model of focal cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1987;50:402–410. doi: 10.1136/jnnp.50.4.402. [PMC free article] [PubMed] [Cross Ref]
  • 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. [PubMed]
  • Yanamoto H, Nagata I, Niitsu Y, Xue JH, Zhang Z, Kikuchi H. Evaluation of MCAO stroke models in normotensive rats: standardized neocortical infarction by the 3VO technique. Exp Neurol. 2003;182:261–274. doi: 10.1016/S0014-4886(03)00116-X. [PubMed] [Cross Ref]
  • Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol. 1985;17:497–504. doi: 10.1002/ana.410170513. [PubMed] [Cross Ref]
  • Dietrich WD, Watson BD, Busto R, Ginsberg MD, Bethea JR. Photochemically induced cerebral infarction. I. Early microvascular alterations. Acta Neuropathol (Berl) 1987;72:315–325. doi: 10.1007/BF00687262. [PubMed] [Cross Ref]
  • Cai H, Yao H, Ibayashi S. Photothrombotic middle cerebral artery occlusion in spontaneously hypertensive rats: influence of substrain, gender, and distal middle cerebral artery patterns on infarct size. Stroke. 1998;29:1982–1986. [PubMed]
  • Hilger T, Blunk JA, Hoehn M, Mies G, Wester P. Characterization of a novel chronic photothrombotic ring stroke model in rats by magnetic resonance imaging, biochemical imaging, and histology. J Cereb Blood Flow Metab. 2004;24:789–797. doi: 10.1097/01.WCB.0000123905.17746.DB. [PubMed] [Cross Ref]
  • Sharkey J, Butcher SP. Characterisation of an experimental model of stroke produced by intracerebral microinjection of endothelin-1 adjacent to the rat middle cerebral artery. J Neurosci Methods. 1995;60:125–131. doi: 10.1016/0165-0270(95)00003-D. [PubMed] [Cross Ref]
  • Macrae IM, Robinson MJ, Graham DI, Reid JL, McCulloch J. Endothelin- 1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences. J Cereb Blood Flow Metab. 1993;13:276–284. [PubMed]
  • Persson L, Hårdemark HG, Bolander HG, Hillered L, Olsson Y. Neurologic and neuropathologic outcome after middle cerebral artery occlusion in rats. Stroke. 1989;20:641–645. [PubMed]
  • Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17:472–476. [PubMed]
  • Hunter AJ, Hatcher J, Virley D, Nelson P, Irving E, Hadingham SJ, Parsons AA. Functional assessments in mice and rats after focal stroke. Neuropharmacology. 2000;39:806–816. doi: 10.1016/S0028-3908(99)00262-2. [PubMed] [Cross Ref]
  • D'Hooge R, DE Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 2001;36:60–90. doi: 10.1016/S0165-0173(01)00067-4. [PubMed] [Cross Ref]
  • Roof RL, Schielke GP, Ren X, Hall ED. A comparison of long-term functional outcome after 2 middle cerebral artery occlusion models in rats. Stroke. 2001;32:2648–2657. doi: 10.1161/hs1101.097397. [PubMed] [Cross Ref]
  • DeBow SB, Clark DL, Maclellan CL, Colbourne F. Incomplete assessment of experimental cytoprotectants in rodent ischemia studies. Can J Neurol Sci. 2003;30:368–374. [PubMed]
  • Bederson JB, Pitts LH, Germano SM, Nishimura MC, Davis RL, Bartkowski HM. Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke. 1986;17:1304–1308. [PubMed]
  • Swanson RA, Sharp FR. Infarct measurement methodology. J Cereb Blood Flow Metab. 1994;14:697–698. [PubMed]

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