Middle Cerebral Artery Occlusion Model in Rodents: Methods and Potential Pitfalls

A variety of animal models have been developed for modeling ischemic stroke. The middle cerebral artery occlusion (MCAO) model has been utilized extensively, especially in rodents. While the MCAO model provides stroke researchers with an excellent platform to investigate the disease, controversial or even paradoxical results are occasionally seen in the literature utilizing this model. Various factors exert important effects on the outcome in this stroke model, including the age and sex of the animal examined. This paper discusses emerging information on the effects of age and sex on ischemic outcomes after MCAO, with an emphasis on mouse models of stroke.

[1]  M. Hoehn,et al.  Application of magnetic resonance to animal models of cerebral ischemia , 2001, Journal of magnetic resonance imaging : JMRI.

[2]  V. Muzykantov,et al.  Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders , 2010, Journal of neurochemistry.

[3]  N. Maeda,et al.  Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Myron D. Ginsberg,et al.  Neuroprotection for ischemic stroke: Past, present and future , 2008, Neuropharmacology.

[5]  M Chopp,et al.  Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. , 1993, The American journal of pathology.

[6]  Jun Li,et al.  Sex differences in caspase activation after stroke. , 2009, Stroke.

[7]  J. Phillis,et al.  Further studies on the effects of topical lactate on amino acid efflux from the ischemic rat cortex , 2001, Brain Research.

[8]  L. McCullough,et al.  Sex differences in the response to activation of the poly (ADP-ribose) polymerase pathway after experimental stroke , 2009, Experimental Neurology.

[9]  Timothy Q Duong,et al.  Differences in Ischemic Lesion Evolution in Different Rat Strains Using Diffusion and Perfusion Imaging , 2005, Stroke.

[10]  D. Duverger,et al.  The Quantification of Cerebral Infarction following Focal Ischemia in the Rat: Influence of Strain, Arterial Pressure, Blood Glucose Concentration, and Age , 1988, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  A. Paganini-Hill Hormone replacement therapy and stroke: risk, protection or no effect? , 2001, Maturitas.

[12]  E. Hall,et al.  Role of animal studies in the design of clinical trials. , 2009, Frontiers of neurology and neuroscience.

[13]  A. Drewnowski,et al.  Journals of Gerontology , 2001 .

[14]  C. Kooperberg,et al.  Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. , 2003, JAMA.

[15]  C. Sudlow,et al.  Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. , 1997, Stroke.

[16]  H. Diener,et al.  Glycine Antagonist (GV150526) in Acute Stroke: A Multicentre, Double-Blind Placebo-Controlled Phase II Trial , 2001, Cerebrovascular Diseases.

[17]  D. Kent,et al.  The gender effect in stroke thrombolysis , 2008, Neurology.

[18]  L. McCullough,et al.  Pharmacological Inhibition of AMP-activated Protein Kinase Provides Neuroprotection in Stroke* , 2005, Journal of Biological Chemistry.

[19]  C. Kooperberg,et al.  Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. , 2003, JAMA.

[20]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[21]  S. Ekholm,et al.  Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. , 1995, Stroke.

[22]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2010 update: a report from the American Heart Association. , 2010, Circulation.

[23]  J. Miller,et al.  Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion. , 1995, Brain research. Molecular brain research.

[24]  L. McCullough,et al.  Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[25]  Michael Benatar,et al.  Methodological Quality of Animal Studies of Neuroprotective Agents Currently in Phase II/III Acute Ischemic Stroke Trials , 2009, Stroke.

[26]  Cathy M. Helgason,et al.  American Heart Association Prevention Conference IV: Prevention and Rehabilitation of Stroke Introduction , 1997 .

[27]  A. Fagan,et al.  17β-Estradiol treatment following permanent focal ischemia does not influence recovery of sensorimotor function , 2006, Neurobiology of Disease.

[28]  W. Hoffman,et al.  The Effect of Sevoflurane and Propofol on Cerebral Neurotransmitter Concentrations During Cerebral Ischemia in Rats , 2003, Anesthesia and analgesia.

[29]  B. Vollrath,et al.  In vivo animal models of cerebral vasospasm: a review. , 2000, Neurosurgery.

[30]  N. Wenger,et al.  Cardiovascular health and disease in women. , 1993, The New England journal of medicine.

[31]  G. Sutherland,et al.  Effect of age in rodent models of focal and forebrain ischemia. , 1996, Stroke.

[32]  L. McCullough,et al.  Changes in Experimental Stroke Outcome across the Life Span , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[33]  L. McCullough,et al.  Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender , 2004, Experimental Neurology.

[34]  C. Franceschi,et al.  Immunogenetics, Gender, and Longevity , 2006, Annals of the New York Academy of Sciences.

[35]  P. Wolf,et al.  American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke. Risk factors. , 1997, Stroke.

[36]  P. Abete,et al.  Ischemic preconditioning in the aging heart: From bench to bedside , 2010, Ageing Research Reviews.

[37]  Ross L Prentice,et al.  Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. , 2005, American journal of epidemiology.

[38]  J. Mariani,et al.  Specific caspase inhibitor Q‐VD‐OPh prevents neonatal stroke in P7 rat: a role for gender , 2007, Journal of neurochemistry.

[39]  N. van Bruggen,et al.  Secondary Reduction in the Apparent Diffusion Coefficient of Water, Increase in Cerebral Blood Volume, and Delayed Neuronal Death after Middle Cerebral Artery Occlusion and Early Reperfusion in the Rat , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  R. Traystman Animal models of focal and global cerebral ischemia. , 2003, ILAR journal.

[41]  S. Thomas Carmichael,et al.  Rodent models of focal stroke: Size, mechanism, and purpose , 2005, NeuroRX.

[42]  A. Tuttolomondo,et al.  Inflammation as a therapeutic target in acute ischemic stroke treatment. , 2009, Current topics in medicinal chemistry.

[43]  N. Plesnila,et al.  Apoptosis-Inducing Factor Triggered by Poly(ADP-Ribose) Polymerase and Bid Mediates Neuronal Cell Death after Oxygen-Glucose Deprivation and Focal Cerebral Ischemia , 2005, The Journal of Neuroscience.

[44]  R. Simon,et al.  Early Detection of DNA Strand Breaks in the Brain After Transient Focal Ischemia: Implications for the Role of DNA Damage in Apoptosis and Neuronal Cell Death , 1997, Journal of neurochemistry.

[45]  E. Theodorsson,et al.  Different methods for administering 17β-estradiol to ovariectomized rats result in opposite effects on ischemic brain damage , 2010, BMC Neuroscience.

[46]  R. Traystman,et al.  Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. , 2000, Stroke.

[47]  J. Hauw,et al.  Predictors for malignant middle cerebral artery infarctions , 2006, Neurology.

[48]  L. McCullough,et al.  Expression of Na–K–Cl cotransporter and edema formation are age dependent after ischemic stroke , 2010, Experimental Neurology.

[49]  S. Yang,et al.  Alzheimer’s disease: the impact of age-related changes in reproductive hormones , 2005, Cellular and Molecular Life Sciences CMLS.

[50]  L. McCullough,et al.  Animal models of ischemic stroke: balancing experimental aims and animal care. , 2004, Comparative medicine.

[51]  J. Roda,et al.  Cerebral Ischemia: From Animal Studies to Clinical Practice. Should the Methods Be Reviewed? , 2001, Cerebrovascular Diseases.

[52]  P. Barber,et al.  Early T1- and T2-weighted MRI signatures of transient and permanent middle cerebral artery occlusion in a murine stroke model studied at 9.4T , 2005, Neuroscience Letters.

[53]  E. Anyanwu,et al.  Neurochemical Changes in the Aging Process: Implications in Medication in the Elderly , 2007, TheScientificWorldJournal.

[54]  P. Barber,et al.  Improved regional cerebral blood flow is important for the protection seen in a mouse model of late phase ischemic preconditioning , 2006, Brain Research.

[55]  J. L. Laprairie,et al.  Female rats are more vulnerable to the long-term consequences of neonatal inflammatory injury , 2007, PAIN.

[56]  Garnet L Anderson,et al.  Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. , 2006, American journal of epidemiology.

[57]  Aspey,et al.  Middle cerebral artery occlusion in the rat: consistent protocol for a model of stroke , 1998, Neuropathology and applied neurobiology.

[58]  C. Siegel,et al.  Sex differences in cerebral ischemia: Possible molecular mechanisms , 2010, Journal of neuroscience research.

[59]  R. Abbate,et al.  Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment , 2009, Thrombosis and Haemostasis.

[60]  L. McCullough,et al.  Estrogen and ischemic neuroprotection: an integrated view , 2003, Trends in Endocrinology & Metabolism.

[61]  L. McCullough,et al.  Sex Differences in Minocycline-Induced Neuroprotection after Experimental Stroke , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[62]  Fudong Liu,et al.  TTC, Fluoro-Jade B and NeuN staining confirm evolving phases of infarction induced by middle cerebral artery occlusion , 2009, Journal of Neuroscience Methods.

[63]  G. Comi,et al.  Animal Models of Ischemic Stroke. Part Two: Modeling Cerebral Ischemia , 2010, The open neurology journal.

[64]  Turgut Tatlisumak,et al.  Acute ischemic stroke: Overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia , 2007, Pharmacology Biochemistry and Behavior.

[65]  E. Roth,et al.  American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke. Rehabilitation. , 1997, Stroke.

[66]  Yea-Ru Yang,et al.  Effect of Age in Rats following Middle Cerebral Artery Occlusion , 2002, Gerontology.

[67]  L. McCullough,et al.  Postischemic Estrogen Reduces Hypoperfusion and Secondary Ischemia After Experimental Stroke , 2001, Stroke.

[68]  David A. Bridwell,et al.  Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions , 2007, Proceedings of the National Academy of Sciences.

[69]  J. Relton,et al.  Peripheral Administration of Interleukin-1 Receptor Antagonist Inhibits Brain Damage after Focal Cerebral Ischemia in the Rat , 1996, Experimental Neurology.

[70]  Robert J. Dempsey,et al.  Infarct volume quantification in mouse focal cerebral ischemia: a comparison of triphenyltetrazolium chloride and cresyl violet staining techniques , 2004, Journal of Neuroscience Methods.

[71]  Jun Li,et al.  Neuroprotective Effects of Adenosine Monophosphate-Activated Protein Kinase Inhibition and Gene Deletion in Stroke , 2007, Stroke.

[72]  L. Schmued,et al.  Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration , 2000, Brain Research.

[73]  E. Cristiano,et al.  Acute ischemic stroke and transient ischemic attack in the very old – risk factor profile and stroke subtype between patients older than 80 years and patients aged less than 80 years , 2007, European journal of neurology.

[74]  Egle Cekanaviciute,et al.  TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke , 2010, Journal of Neuroinflammation.

[75]  A Pasqualin,et al.  Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa. , 1999, Journal of neurosurgery.

[76]  Joanne M. Smith,et al.  Stroke in the female: role of biological sex and estrogen. , 2004, ILAR journal.

[77]  L. McCullough,et al.  Pathways to ischemic neuronal cell death: are sex differences relevant? , 2008, Journal of Translational Medicine.

[78]  S. Ashwal,et al.  Animal models of neonatal stroke , 2001, Current opinion in pediatrics.

[79]  R. Lobo Menopause and stroke and the effects of hormonal therapy , 2007, Climacteric : the journal of the International Menopause Society.

[80]  P. Hurn,et al.  Effects of Combined Estrogen and Progesterone on Brain Infarction in Reproductively Senescent Female Rats , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[81]  P. Wolf,et al.  Risk factors : Prevention and Rehabilitation of Stroke , 1997 .

[82]  A. Kharlamov,et al.  Age-dependent increase in infarct volume following photochemically induced cerebral infarction: putative role of astroglia. , 2000, The journals of gerontology. Series A, Biological sciences and medical sciences.

[83]  P A Wolf,et al.  American Heart Association Prevention Conference IV: prevention and rehabilitation of stroke: executive summary. , 1997, Circulation.

[84]  R. Traystman,et al.  Cognitive and behavioral assessment in experimental stroke research: will it prove useful? , 2001, Neuroscience & Biobehavioral Reviews.

[85]  L. McCullough,et al.  Fluoro-Jade B and NeuN staining confirm evolving phases of infarction induced by Middle Cerebral Artery Occlusion , 2009 .

[86]  K. Furie,et al.  Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2007, Circulation.

[87]  I Bergmann,et al.  Computed Tomography in Prognostic Stroke Evaluation , 1992, Stroke.

[88]  M. Puerto,et al.  Changes with ageing in several leukocyte functions of male and female rats , 2004, Biogerontology.

[89]  T. Nabika,et al.  The Stroke-Prone Spontaneously Hypertensive Rat: How Good Is It as a Model for Cerebrovascular Diseases? , 2004, Cellular and Molecular Neurobiology.

[90]  A. Algra,et al.  Predictors of Life-Threatening Brain Edema in Middle Cerebral Artery Infarction , 2008, Cerebrovascular Diseases.

[91]  T. Kadar,et al.  Aging has a complex effect on a rat model of ischemic stroke , 2002, Brain Research.

[92]  B. Crain,et al.  Cognitive deficits after focal cerebral ischemia in mice. , 2000, Stroke.