Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter February 5, 2018

Experimental models of focal and multifocal cerebral ischemia: a review

Kristy L. Meadows ORCID logo


Rodent and rabbit stroke models have been instrumental in our current understanding of stroke pathophysiology; however, translational failure is a significant problem in preclinical ischemic stroke research today. There are a number of different focal cerebral ischemia models that vary in their utility, pathophysiology of causing disease, and their response to treatments. Unfortunately, despite active preclinical research using these models, treatment options for ischemic stroke have not significantly advanced since the food and drug administration approval of tissue plasminogen activator in 1996. This review aims to summarize current stroke therapies, the preclinical experimental models used to help develop stroke therapies, as well as their advantages and limitations. In addition, this review discusses the potential for naturally occurring canine ischemic stroke models to compliment current preclinical models and to help bridge the translational gap between small mammal models and human clinical trials.


I would like to thank Dr. Robert Bridges and Dr. Sandra Ayres for their thoughtful comments on this manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

  1. Conflict of interest statement: The author has no conflicts of interest.


Albers, G.W., von Kummer, R., Truelsen, T., Jensen, J.-K.S., Ravn, G.M., Grønning, B.A., Chabriat, H., Chang, K.-C., Davalos, A.E., Ford, G.A., et al. (2015). Safety and efficacy of desmoteplase given 3–9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Neurol. 14, 575–584.10.1016/S1474-4422(15)00047-2Search in Google Scholar PubMed

Altay, U.M., Skerritt, G.C., Hilbe, M., Ehrensperger, F., and Steffen, F. (2011). Feline cerebrovascular disease: clinical and histopathologic findings in 16 cats. J. Am. Anim. Hosp. Assoc. 47, 89–97.10.5326/JAAHA-MS-5480Search in Google Scholar PubMed

Angeleri, F., Angeleri, V.A., Foschi, N., Giaquinto, S., and Nolfe, G. (1993). The influence of depression, social activity, and family stress on functional outcome after stroke. Stroke J. Cereb. Circ. 24, 1478–1483.10.1161/01.STR.24.10.1478Search in Google Scholar

Ansari, S., Azari, H., Caldwell, K.J., Regenhardt, R.W., Hedna, V.S., Waters, M.F., Hoh, B.L., and Mecca, A.P. (2013). Endothelin-1 induced middle cerebral artery occlusion model for ischemic stroke with laser Doppler flowmetry guidance in rat. J. Vis. Exp. 72, 1–6, pii: 50014.10.3791/50014Search in Google Scholar PubMed PubMed Central

Atchaneeyasakul, K., Guada, L., Ramdas, K., Watanabe, M., Bhattacharya, P., Raval, A.P., and Yavagal, D.R. (2016). Large animal canine endovascular ischemic stroke models: a review. Brain Res. Bull. 127, 134–140.10.1016/j.brainresbull.2016.07.006Search in Google Scholar PubMed

Awano, T., Johnson, G.S., Wade, C.M., Katz, M.L., Johnson, G.C., Taylor, J.F., Perloski, M., Biagi, T., Baranowska, I., Long, S., et al. (2009). Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 106, 2794–2799.10.1073/pnas.0812297106Search in Google Scholar PubMed PubMed Central

Bacigaluppi, M., Comi, G., and Hermann, D.M. (2010). Animal models of ischemic stroke. Part two: modeling cerebral ischemia. Open Neurol. J. 4, 34.10.2174/1874205X01004010034Search in Google Scholar PubMed

Barton, M., Traupe, T., and Haudenschild, C.C. (2003). Endothelin, hypercholesterolemia and atherosclerosis. Coron. Artery Dis. 14, 477–490.10.1097/00019501-200311000-00002Search in Google Scholar PubMed

Bederson, J.B., Pitts, L.H., Germano, S.M., Nishimura, M.C., Davis, R.L., and Bartkowski, H.M. (1986). Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17, 1304–1308.10.1161/01.STR.17.6.1304Search in Google Scholar PubMed

Bednar, M.M., McAuliffe, T., Raymond, S., and Gross, C.E. (1990). Tissue plasminogen activator reduces brain injury in a rabbit model of thromboembolic stroke. Stroke 21, 1705–1709.10.1161/01.STR.21.12.1705Search in Google Scholar

Belayev, L., Alonso, O.F., Busto, R., Zhao, W., and Ginsberg, M.D. (1996). Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke J. Cereb. Circ. 27, 1616–1622; discussion 1623.10.1161/01.STR.27.9.1616Search in Google Scholar PubMed

Beltran, W.A., Cideciyan, A.V., Iwabe, S., Swider, M., Kosyk, M.S., McDaid, K., Martynyuk, I., Ying, G.-S., Shaffer, J., Deng, W.-T., et al. (2015). Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease. Proc. Natl. Acad. Sci. USA 112, E5844–E5853.10.1073/pnas.1509914112Search in Google Scholar PubMed PubMed Central

Berkhemer, O.A., Fransen, P.S.S., Beumer, D., van den Berg, L.A., Lingsma, H.F., Yoo, A.J., Schonewille, W.J., Vos, J.A., Nederkoorn, P.J., Wermer, M.J.H., et al. (2015). A randomized trial of intraarterial treatment for acute ischemic stroke. N. Engl. J. Med. 372, 11–20.10.1056/NEJMoa1411587Search in Google Scholar PubMed

Biernaskie, J., Corbett, D., Peeling, J., Wells, J., and Lei, H. (2001). A serial MR study of cerebral blood flow changes and lesion development following endothelin-1-induced ischemia in rats. Magn. Reson. Med. 46, 827–830.10.1002/mrm.1263Search in Google Scholar PubMed

Boyko, M., Kutz, R., Gruenbaum, B.F., Cohen, H., Kozlovsky, N., Gruenbaum, S.E., Shapira, Y., and Zlotnik, A. (2013). The influence of aging on poststroke depression using a rat model via middle cerebral artery occlusion. Cogn. Affect. Behav. Neurosci. 13, 847–859.10.3758/s13415-013-0177-3Search in Google Scholar PubMed

Braeuninger, S. and Kleinschnitz, C. (2009). Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems. Exp. Transl. Stroke Med. 1, 8.10.1186/2040-7378-1-8Search in Google Scholar PubMed PubMed Central

Brint, S., Jacewicz, M., Kiessling, M., Tanabe, J., and Pulsinelli, W. (1988). 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. 8, 474–485.10.1038/jcbfm.1988.88Search in Google Scholar PubMed

Broussalis, E., Killer, M., McCoy, M., Harrer, A., Trinka, E., and Kraus, J. (2012). Current therapies in ischemic stroke. Part A. Recent developments in acute stroke treatment and in stroke prevention. Drug Discov. Today 17, 296–309.10.1016/j.drudis.2011.11.005Search in Google Scholar PubMed

Campbell, B.C.V., Mitchell, P.J., Kleinig, T.J., Dewey, H.M., Churilov, L., Yassi, N., Yan, B., Dowling, R.J., Parsons, M.W., Oxley, T.J., et al. (2015). Endovascular therapy for ischemic stroke with perfusion-imaging selection. N. Engl. J. Med. 372, 1009–1018.10.1056/NEJMoa1414792Search in Google Scholar PubMed

Carmichael, S.T. (2005). Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2, 396–409.10.1602/neurorx.2.3.396Search in Google Scholar PubMed PubMed Central

Carvalho, A., Cunha, A., Rodrigues, M., Figueiredo, S., Paredes, L., Gregório, T., Morais, H., Pinheiro, J., Cruz, V.T., Roriz, J.M., et al. (2017). Mechanical thrombectomy in acute ischemic stroke: initial single-center experience and comparison with randomized controlled trials. J. Stroke Cerebrovasc. Dis. 26, 589–594.10.1016/j.jstrokecerebrovasdis.2016.11.116Search in Google Scholar PubMed

Coates, J.R. and Wininger, F.A. (2010). Canine degenerative myelopathy. Vet. Clin. North Am. Small Anim. Pract. 40, 929–950.10.1016/j.cvsm.2010.05.001Search in Google Scholar PubMed

Cook, D.J. and Tymianski, M. (2011). Translating promising preclinical neuroprotective therapies to human stroke trials. Expert Rev. Cardiovasc. Ther. 9, 433–449.10.1586/erc.11.34Search in Google Scholar PubMed

Cook, D.J. and Tymianski, M. (2012). Nonhuman primate models of stroke for translational neuroprotection research. Neurotherapeutics 9, 371–379.10.1007/s13311-012-0115-zSearch in Google Scholar PubMed

Cook, D.J., Teves, L., and Tymianski, M. (2012). Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483, 213–217.10.1038/nature10841Search in Google Scholar PubMed

Crisp, M.J., Beckett, J., Coates, J.R., and Miller, T.M. (2013). Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model. Exp. Neurol. 248, 1–9.10.1016/j.expneurol.2013.05.009Search in Google Scholar PubMed

Culp, W.C., Brown, A.T., Lowery, J.D., Arthur, M.C., Roberson, P.K., and Skinner, R.D. (2015). Dodecafluoropentane emulsion extends window for tPA therapy in a rabbit stroke model. Mol. Neurobiol. 52, 979–984.10.1007/s12035-015-9243-xSearch in Google Scholar

Davis, P.R. and Head, E. (2014). Prevention approaches in a preclinical canine model of Alzheimer’s disease: benefits and challenges. Front. Pharmacol. 5, 1–14.10.3389/fphar.2014.00047Search in Google Scholar

Deb, P., Sharma, S., and Hassan, K.M. (2010). Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 17, 197–218.10.1016/j.pathophys.2009.12.001Search in Google Scholar PubMed

del Zoppo, G.J. and Hallenbeck, J.M. (2000). Advances in the vascular pathophysiology of ischemic stroke. Thromb. Res. 98, 73–81.10.1016/S0049-3848(00)00218-8Search in Google Scholar PubMed

dela Peña, I.C., Yoo, A., Tajiri, N., Acosta, S.A., Ji, X., Kaneko, Y., and Borlongan, C.V. (2015). Granulocyte colony-stimulating factor attenuates delayed tPA-induced hemorrhagic transformation in ischemic stroke rats by enhancing angiogenesis and vasculogenesis. J. Cereb. Blood Flow Metab. 35, 338–346.10.1038/jcbfm.2014.208Search in Google Scholar PubMed

Dirnagl, U. (2010). Rodent Models of Stroke (New York, N.Y: Humana Press).10.1007/978-1-60761-750-1Search in Google Scholar

Donnan, G.A., Fisher, M., Macleod, M., and Davis, S.M. (2008). Stroke. Lancet 371, 1612–1623.10.1016/S0140-6736(08)60694-7Search in Google Scholar PubMed

Dschietzig, T., Bartsch, C., Richter, C., Laule, M., Baumann, G., and Stangl, K. (2003). Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-κB. Circ. Res. 92, 32–40.10.1161/01.RES.0000051884.27117.7ESearch in Google Scholar PubMed

Dumitrascu, O.M., Lamb, J., and Lyden, P.D. (2016). Still cooling after all these years: meta-analysis of pre-clinical trials of therapeutic hypothermia for acute ischemic stroke. J. Cereb. Blood Flow Metab. 36, 1157–1164.10.1177/0271678X16645112Search in Google Scholar PubMed PubMed Central

Durukan, A., and Tatlisumak, T. (2007). Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol. Biochem. Behav. 87, 179–197.10.1016/j.pbb.2007.04.015Search in Google Scholar PubMed

Fisher, M., Feuerstein, G., Howells, D.W., Hurn, P.D., Kent, T.A., Savitz, S.I., Lo, E.H., and STAIR Group (2009). Update of the Stroke Therapy Academic Industry Roundtable preclinical recommendations. Stroke J. Cereb. Circ. 40, 2244–2250.10.1161/STROKEAHA.108.541128Search in Google Scholar PubMed PubMed Central

Fluri, F., Schuhmann, M.K., and Kleinschnitz, C. (2015). Animal models of ischemic stroke and their application in clinical research. Drug Des. Devel. Ther. 9, 3445–3454.10.2147/DDDT.S56071Search in Google Scholar PubMed PubMed Central

Garosi, L.S. (2010). Cerebrovascular disease in dogs and cats. Vet. Clin. North Am. Small Anim. Pract. 40, 65–79.10.1016/j.cvsm.2009.09.001Search in Google Scholar PubMed

Garosi, L.S. and McConnell, J.F. (2005). Ischaemic stroke in dogs and humans: a comparative review. J. Small Anim. Pract. 46, 521–529.10.1111/j.1748-5827.2005.tb00281.xSearch in Google Scholar PubMed

Garosi, L., McConnell, J.F., Platt, S.R., Barone, G., Baron, J.C., de Lahunta, A., and Schatzberg, S.J. (2006). Clinical and topographic magnetic resonance characteristics of suspected brain infarction in 40 dogs. J. Vet. Intern. Med. Am. Coll. Vet. Intern. Med. 20, 311–321.10.1111/j.1939-1676.2006.tb02862.xSearch in Google Scholar

Gibson, C.L. and Attwood, L. (2016). The impact of gender on stroke pathology and treatment. Neurosci. Biobehav. Rev. 67, 119–24.10.1016/j.neubiorev.2015.08.020Search in Google Scholar PubMed

Gibson, C.L., Coomber, B., and Rathbone, J. (2009). Is progesterone a candidate neuroprotective factor for treatment following ischemic stroke? Neurosci. Rev. J. Bringing Neurobiol. Neurol. Psychiatry 15, 324–332.Search in Google Scholar

Gounis, M.J., Wakhloo, A.K., and Chueh, J.-Y. (2013a). Preclinical investigations for thrombectomy devices – does it translate to humans? Stroke 44, S7–S10.10.1161/STROKEAHA.111.000692Search in Google Scholar PubMed

Gounis, M.J., Nogueira, R.G., Mehra, M., Chueh, J., and Wakhloo, A.K. (2013b). A thromboembolic model for the efficacy and safety evaluation of combined mechanical and pharmacologic revascularization strategies. J. NeuroInterventional Surg. 5, i85–i89.10.1136/neurintsurg-2012-010435Search in Google Scholar PubMed PubMed Central

Goyal, M., Demchuk, A.M., Menon, B.K., Eesa, M., Rempel, J.L., Thornton, J., Roy, D., Jovin, T.G., Willinsky, R.A., Sapkota, B.L., et al. (2015). Randomized assessment of rapid endovascular treatment of ischemic stroke. N. Engl. J. Med. 372, 1019–1030.10.1056/NEJMoa1414905Search in Google Scholar PubMed

Gredal, H., Skerritt, G.C., Gideon, P., Arlien-Soeborg, P., and Berendt, M. (2013a). Spontaneous ischaemic stroke in dogs: clinical topographic similarities to humans. Acta Neurol. Scand. 128, e11–e16.10.1111/ane.12092Search in Google Scholar PubMed

Gredal, H., Toft, N., Westrup, U., Motta, L., Gideon, P., Arlien-Søborg, P., Skerritt, G.C., and Berendt, M. (2013b). Survival and clinical outcome of dogs with ischaemic stroke. Vet. J. 196, 408–413.10.1016/j.tvjl.2012.10.018Search in Google Scholar PubMed

Greenberg, D.A. (2013). Preclinical stroke research: gains and gaps. Stroke J. Cereb. Circ. 44, S114–S115.10.1161/STROKEAHA.113.002088Search in Google Scholar PubMed PubMed Central

Guajardo, V.D., Terroni, L., Sobreiro, M. de F.M., Zerbini, M.I. dos S., Tinone, G., Scaff, M., Iosifescu, D.V., de Lucia, M.C.S., and Fráguas, R. (2015). The influence of depressive symptoms on quality of life after stroke: a prospective study. J. Stroke Cerebrovasc. Dis. 24, 201–209.10.1016/j.jstrokecerebrovasdis.2014.08.020Search in Google Scholar PubMed

Head, E., Nukala, V.N., Fenoglio, K.A., Muggenburg, B.A., Cotman, C.W., and Sullivan, P.G. (2009). Effects of age, dietary, and behavioral enrichment on brain mitochondria in a canine model of human aging. Exp. Neurol. 220, 171–176.10.1016/j.expneurol.2009.08.014Search in Google Scholar PubMed PubMed Central

Hemmen, T.M., Raman, R., Guluma, K.Z., Meyer, B.C., Gomes, J.A., Cruz-Flores, S., Wijman, C.A., Rapp, K.S., Grotta, J.C., Lyden, P.D., et al. (2010). Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke 41, 2265–2270.10.1161/STROKEAHA.110.592295Search in Google Scholar PubMed PubMed Central

Hoffman, J.M., Creevy, K.E., and Promislow, D.E.L. (2013). Reproductive capability is associated with lifespan and cause of death in companion dogs. PloS One 8, e61082.10.1371/journal.pone.0061082Search in Google Scholar PubMed PubMed Central

Hossmann, K.-A. (2008). Cerebral ischemia: models, methods and outcomes. Neuropharmacology 55, 257–270.10.1016/j.neuropharm.2007.12.004Search in Google Scholar PubMed

Iadecola, C., and Anrather, J. (2011). Stroke research at a crossroad: asking the brain for directions. Nat. Neurosci. 14, 1363–1368.10.1038/nn.2953Search in Google Scholar PubMed PubMed Central

Jeon, J.-H., Jung, H.-W., Jang, H.-M., Moon, J.-H., Park, K.-T., Lee, H.-C., Lim, H.-Y., Sur, J.-H., Kang, B.-T., Ha, J., et al. (2015). Canine model of ischemic stroke with permanent middle cerebral artery occlusion: clinical features, magnetic resonance imaging, histopathology, and immunohistochemistry. J. Vet. Sci. 16, 75.10.4142/jvs.2015.16.1.75Search in Google Scholar PubMed PubMed Central

Joshi, C.N., Jain, S.K., and Murthy, P.S.R. (2004). An optimized triphenyltetrazolium chloride method for identification of cerebral infarcts. Brain Res. Protoc. 13, 11–17.10.1016/j.brainresprot.2003.12.001Search in Google Scholar PubMed

Jovin, T.G., Chamorro, A., Cobo, E., de Miquel, M.A., Molina, C.A., Rovira, A., San Román, L., Serena, J., Abilleira, S., Ribó, M., et al. (2015). Thrombectomy within 8 hours after symptom onset in ischemic stroke. N. Engl. J. Med. 372, 2296–2306.10.1056/NEJMoa1503780Search in Google Scholar PubMed

Kalogeris, T., Baines, C.P., Krenz, M., and Korthuis, R.J. (2012). Cell biology of ischemia/reperfusion injury. Int. Rev. Cell Mol. Biol. 298, 229–317.10.1016/B978-0-12-394309-5.00006-7Search in Google Scholar PubMed PubMed Central

Kandel, E.R., Schwartz, J.H., Jessell, T.M., Siegelbaum, S.A., and Hudspeth A.J. (2013). Principles of Neural Science (New York: McGraw-Hill).Search in Google Scholar

Kedzierski, R.M. and Yanagisawa, M. (2001). Endothelin system: the double-edged sword in health and disease. Annu. Rev. Pharmacol. Toxicol. 41, 851–876.10.1146/annurev.pharmtox.41.1.851Search in Google Scholar PubMed

Krieger, D.W., Georgia, M.A.D., Abou-Chebl, A., Andrefsky, J.C., Sila, C.A., Katzan, I.L., Mayberg, M.R., and Furlan, A.J. (2001). Cooling for acute ischemic brain damage (COOL AID) – an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 32, 1847–1854.10.1161/01.STR.32.8.1847Search in Google Scholar PubMed

Kronenberg, G., Gertz, K., Heinz, A., and Endres, M. (2014). Of mice and men: modelling post-stroke depression experimentally. Br. J. Pharmacol. 171, 4673–4689.10.1111/bph.12775Search in Google Scholar PubMed PubMed Central

Kumar, M.S.A. (2013). Clinically Oriented Anatomy of the Dog & Cat (Ronkonkoma, NY, USA: Linus Publications).Search in Google Scholar

Kunz, A., Dirnagl, U., and Mergenthaler, P. (2010). Acute pathophysiological processes after ischaemic and traumatic brain injury. Best Pract. Res. Clin. Anaesthesiol. 24, 495–509.10.1016/j.bpa.2010.10.001Search in Google Scholar PubMed

Lang, J.T. and McCullough, L.D. (2008). Pathways to ischemic neuronal cell death: are sex differences relevant? J. Transl. Med. 6, 33.10.1186/1479-5876-6-33Search in Google Scholar PubMed PubMed Central

Levy, D.E., del Zoppo, G.J., Demaerschalk, B.M., Demchuk, A.M., Diener, H.-C., Howard, G., Kaste, M., Pancioli, A.M., Ringelstein, E.B., Spatareanu, C., et al. (2009). Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program. Stroke J. Cereb. Circ. 40, 3796–3803.10.1161/STROKEAHA.109.565119Search in Google Scholar PubMed

Lhériteau, E., Petit, L., Weber, M., Le Meur, G., Deschamps, J.-Y., Libeau, L., Mendes-Madeira, A., Guihal, C., François, A., Guyon, R., et al. (2014). Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy. Mol. Ther. J. Am. Soc. Gene Ther. 22, 265–277.10.1038/mt.2013.232Search in Google Scholar PubMed PubMed Central

Lindner, M.D., Gribkoff, V.K., Donlan, N.A., and Jones, T.A. (2003). Long-lasting functional disabilities in middle-aged rats with small cerebral infarcts. J. Neurosci. 23, 10913–10922.10.1523/JNEUROSCI.23-34-10913.2003Search in Google Scholar PubMed

Liu, F. and McCullough, L.D. (2011). Middle cerebral artery occlusion model in rodents: methods and potential pitfalls. J. Biomed. Biotechnol. 2011, 1–9.10.1155/2011/464701Search in Google Scholar PubMed PubMed Central

Liu, F. and McCullough, L.D. (2012). Interactions between age, sex, and hormones in experimental ischemic stroke. Neurochem. Int. 61, 1255–1265.10.1016/j.neuint.2012.10.003Search in Google Scholar PubMed PubMed Central

Liu, R. and Yang, S.-H. (2013). Window of opportunity: estrogen as a treatment for ischemic stroke. Brain Res. 1514, 83–90.10.1016/j.brainres.2013.01.023Search in Google Scholar PubMed PubMed Central

Liu, F., Schafer, D.P., and McCullough, L.D. (2009a). TTC, Fluoro-Jade B and NeuN staining confirm evolving phases of infarction induced by middle cerebral artery occlusion. J. Neurosci. Methods 179, 1–8.10.1016/j.jneumeth.2008.12.028Search in Google Scholar PubMed PubMed Central

Liu, F., Yuan, R., Benashski, S.E., and McCullough, L.D. (2009b). Changes in experimental stroke outcome across the life span. J. Cereb. Blood Flow Metab. 29, 792–802.10.1038/jcbfm.2009.5Search in Google Scholar PubMed PubMed Central

Lo, E.H. (2008a). A new penumbra: transitioning from injury into repair after stroke. Nat. Med. 14, 497–500.10.1038/nm1735Search in Google Scholar PubMed

Lo, E.H. (2008b). Experimental models, neurovascular mechanisms and translational issues in stroke research. Br. J. Pharmacol. 153 (Suppl. 1), S396–S405.10.1038/sj.bjp.0707626Search in Google Scholar PubMed PubMed Central

Longa, E.Z., Weinstein, P.R., Carlson, S., and Cummins, R. (1989). Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke J. Cereb. Circ. 20, 84–91.10.1161/01.STR.20.1.84Search in Google Scholar PubMed

Lucke-Wold, B.P., Turner, R.C., Lucke-Wold, A.N., Rosen, C.L., and Huber, J.D. (2012). Age and the metabolic syndrome as risk factors for ischemic stroke: improving preclinical models of ischemic stroke. Yale J. Biol. Med. 85, 523–539.Search in Google Scholar PubMed

Lyden, P., Hemmen, T., Grotta, J., Rapp, K., Ernstrom, K., Rzesiewicz, T., Parker, S., Concha, M., Hussain, S., and Agarwal, S. (2016). Results of the ICTuS 2 trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke 47, 2888–2895.10.1161/STROKEAHA.116.014200Search in Google Scholar PubMed PubMed Central

Macrae, I.M. (2011). Preclinical stroke research – advantages and disadvantages of the most common rodent models of focal ischaemia. Br. J. Pharmacol. 164, 1062–1078.10.1111/j.1476-5381.2011.01398.xSearch in Google Scholar PubMed PubMed Central

Macrae, I.M., Robinson, M.J., Graham, D.I., Reid, J.L., and McCulloch, J. (1993). Endothelin-1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences. J. Cereb. Blood Flow Metab. 13, 276–284.10.1038/jcbfm.1993.34Search in Google Scholar PubMed

Marshall, J.W.B., Cummings, R.M., Bowes, L.J., Ridley, R.M., and Green, A.R. (2003). Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke 34, 2228–2233.10.1161/01.STR.0000087790.79851.A8Search in Google Scholar PubMed

Martin-Schild, S., Hallevi, H., Shaltoni, H., Barreto, A.D., Gonzales, N.R., Aronowski, J., Savitz, S.I., and Grotta, J.C. (2009). Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia. J. Stroke Cerebrovasc. Dis. 18, 86–96.10.1016/j.jstrokecerebrovasdis.2008.09.015Search in Google Scholar PubMed PubMed Central

Minnerup, J., Wersching, H., Teuber, A., Wellmann, J., Eyding, J., Weber, R., Reimann, G., Weber, W., Krause, L.U., Kurth, T., et al. (2016). Outcome after thrombectomy and intravenous thrombolysis in patients with acute ischemic stroke: a prospective observational study. Stroke 47, 1584–1592.10.1161/STROKEAHA.116.012619Search in Google Scholar PubMed

Moskowitz, M.A., Lo, E.H., and Iadecola, C. (2010). The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198.10.1016/j.neuron.2010.07.002Search in Google Scholar PubMed PubMed Central

Mozaffarian, D., Benjamin, E.J., Go, A.S., Arnett, D.K., Blaha, M.J., Cushman, M., Das, S.R., de Ferranti, S., Després, J.-P., Fullerton, H.J., et al. (2016). Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 133, e38–e360.10.1161/CIR.0000000000000350Search in Google Scholar PubMed

Murata, Y., Rosell, A., Scannevin, R.H., Rhodes, K.J., Wang, X., and Lo, E.H. (2008). Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 39, 3372–3377.10.1161/STROKEAHA.108.514026Search in Google Scholar PubMed PubMed Central

Neuhaus, A.A., Rabie, T., Sutherland, B.A., Papadakis, M., Hadley, G., Cai, R., and Buchan, A.M. (2014). Importance of preclinical research in the development of neuroprotective strategies for ischemic stroke. J. Am. Med. Assoc. Neurol. 71, 634–639.10.1001/jamaneurol.2013.6299Search in Google Scholar PubMed

Nikolova, S., Moyanova, S., Hughes, S., Bellyou-Camilleri, M., Lee, T.-Y., and Bartha, R. (2009). Endothelin-1 induced MCAO: dose dependency of cerebral blood flow. J. Neurosci. Methods 179, 22–28.10.1016/j.jneumeth.2009.01.009Search in Google Scholar PubMed

Opii, W.O., Joshi, G., Head, E., Milgram, N.W., Muggenburg, B.A., Klein, J.B., Pierce, W.M., Cotman, C.W., and Butterfield, D.A. (2008). Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: relevance to Alzheimer’s disease. Neurobiol. Aging 29, 51–70.10.1016/j.neurobiolaging.2006.09.012Search in Google Scholar PubMed PubMed Central

Pääkkönen, T. and Leppäluoto, J. (2002). Cold exposure and hormonal secretion: a review. Int. J. Circumpolar Health 61, 265–276.10.3402/ijch.v61i3.17474Search in Google Scholar PubMed

Paoloni, M. and Khanna, C. (2008). Translation of new cancer treatments from pet dogs to humans. Nat. Rev. Cancer 8, 147–156.10.1038/nrc2273Search in Google Scholar PubMed

Peña, I. dela, Borlongan, C., Shen, G., and Davis, W. (2017). Strategies to extend thrombolytic time window for ischemic stroke treatment: an unmet clinical need. J. Stroke 19, 50–60.10.5853/jos.2016.01515Search in Google Scholar PubMed PubMed Central

Petit, L., Lhériteau, E., Weber, M., Le Meur, G., Deschamps, J.-Y., Provost, N., Mendes-Madeira, A., Libeau, L., Guihal, C., Colle, M.-A., et al. (2012). Restoration of vision in the pde6β-deficient dog, a large animal model of rod-cone dystrophy. Mol. Ther. J. Am. Soc. Gene Ther. 20, 2019–2030.10.1038/mt.2012.134Search in Google Scholar PubMed PubMed Central

Phillips, D.A., Davis, M.A., and Fisher, M. (1988). Selective embolization and clot dissolution with tPA in the internal carotid artery circulation of the rabbit. Am. J. Neuroradiol. 9, 899–902.Search in Google Scholar

Pinho, S.S., Carvalho, S., Cabral, J., Reis, C.A., and Gärtner, F. (2012). Canine tumors: a spontaneous animal model of human carcinogenesis. Transl. Res. J. Lab. Clin. Med. 159, 165–172.10.1016/j.trsl.2011.11.005Search in Google Scholar

Popp, A., Jaenisch, N., Witte, O.W., and Frahm, C. (2009). Identification of ischemic regions in a rat model of stroke. PLoS One 4, e4764.10.1371/journal.pone.0004764Search in Google Scholar

Rankin, K.S., Starkey, M., Lunec, J., Gerrand, C.H., Murphy, S., and Biswas, S. (2012). Of dogs and men: comparative biology as a tool for the discovery of novel biomarkers and drug development targets in osteosarcoma. Pediatr. Blood Cancer 58, 327–333.10.1002/pbc.23341Search in Google Scholar PubMed

Rink, C., Christoforidis, G., Khanna, S., Peterson, L., Patel, Y., Khanna, S., Abduljalil, A., Irfanoglu, O., Machiraju, R., Bergdall, V.K., et al. (2011). Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis. J. Cereb. Blood Flow Metab. 31, 2218–2230.10.1038/jcbfm.2011.85Search in Google Scholar PubMed

Rowell, J.L., McCarthy, D.O., and Alvarez, C.E. (2011). Dog models of naturally occurring cancer. Trends Mol. Med. 17, 380–388.10.1016/j.molmed.2011.02.004Search in Google Scholar PubMed

Russell, D., Madden, K.P., Clark, W.M., and Zivin, J.A. (1992). Tissue plasminogen activator cerebrovascular thrombolysis in rabbits is dependent on the rate and route of administration. Stroke 23, 388–393.10.1161/01.STR.23.3.388Search in Google Scholar PubMed

Saver, J.L., Goyal, M., Bonafe, A., Diener, H.-C., Levy, E.I., Pereira, V.M., Albers, G.W., Cognard, C., Cohen, D.J., Hacke, W., et al. (2015). Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N. Engl. J. Med. 372, 2285–2295.10.1056/NEJMoa1415061Search in Google Scholar PubMed

Schaar, K.L., Brenneman, M.M., and Savitz, S.I. (2010). Functional assessments in the rodent stroke model. Exp. Transl. Stroke Med. 2, 13.10.1186/2040-7378-2-13Search in Google Scholar PubMed

Sharkey, J. and Butcher, S.P. (1995). Characterisation of an experimental model of stroke produced by intracerebral microinjection of endothelin-1 adjacent to the rat middle cerebral artery. J. Neurosci. Methods 60, 125–131.10.1016/0165-0270(95)00003-DSearch in Google Scholar PubMed

Sharkey, J., Ritchie, I.M., Kelly, P.A., and others (1993). Perivascular microapplication of endothelin-1: a new model of focal cerebral ischaemia in the rat. J. Cereb. Blood Flow Metab. 13, 865–865.10.1038/jcbfm.1993.108Search in Google Scholar PubMed

Shuaib, A., Lees, K.R., Lyden, P., Grotta, J., Davalos, A., Davis, S.M., Diener, H.-C., Ashwood, T., Wasiewski, W.W., Emeribe, U., et al. (2007). NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med. 357, 562–571.10.1056/NEJMoa070240Search in Google Scholar PubMed

Sommer, C.J. (2017). Ischemic stroke: experimental models and reality. Acta Neuropathol. (Berl.) 133, 245–261.10.1007/s00401-017-1667-0Search in Google Scholar PubMed PubMed Central

Spratt, N.J., Fernandez, J., Chen, M., Rewell, S., Cox, S., van Raay, L., Hogan, L., and Howells, D.W. (2006). Modification of the method of thread manufacture improves stroke induction rate and reduces mortality after thread-occlusion of the middle cerebral artery in young or aged rats. J. Neurosci. Methods 155, 285–290.10.1016/j.jneumeth.2006.01.020Search in Google Scholar PubMed

Ström, J.O., Ingberg, E., Theodorsson, A., and Theodorsson, E. (2013). Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis. BMC Neurosci. 14, 1–24.10.1186/1471-2202-14-41Search in Google Scholar PubMed PubMed Central

Swanson, R.A., Morton, M.T., Tsao-Wu, G., Savalos, R.A., Davidson, C., and Sharp, F.R. (1990). A semiautomated method for measuring brain infarct volume. J. Cereb. Blood Flow Metab. 10, 290–293.10.1038/jcbfm.1990.47Search in Google Scholar PubMed

Tan, Z., Lucke-Wold, B.P., Logsdon, A.F., Turner, R.C., Tan, C., Li, X., Hongpaison, J., Alkon, D.L., Simpkins, J.W., Rosen, C.L., et al. (2015). Bryostatin extends tPA time window to 6h following middle cerebral artery occlusion in aged female rats. Eur. J. Pharmacol. 764, 404–412.10.1016/j.ejphar.2015.07.035Search in Google Scholar PubMed PubMed Central

Tang, X.N. and Yenari, M.A. (2010). Hypothermia as a cytoprotective strategy in ischemic tissue injury. Ageing Res. Rev. 9, 61–68.10.1016/j.arr.2009.10.002Search in Google Scholar PubMed PubMed Central

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995). Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587.10.1056/NEJM199512143332401Search in Google Scholar PubMed

Thomsen, B.B., Gredal, H., Wirenfeldt, M., Kristensen, B.W., Clausen, B.H., Larsen, A.E., Finsen, B., Berendt, M., and Lambertsen, K.L. (2017). Spontaneous ischaemic stroke lesions in a dog brain: neuropathological characterisation and comparison to human ischaemic stroke. Acta Vet. Scand. 59, 7.10.1186/s13028-016-0275-7Search in Google Scholar PubMed PubMed Central

van der Worp, H.B., Sena, E.S., Donnan, G.A., Howells, D.W., and Macleod, M.R. (2007). Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain 130, 3063–3074.10.1093/brain/awm083Search in Google Scholar PubMed

van der Worp, H.B., Macleod, M.R., Kollmar, R., and European Stroke Research Network for Hypothermia (EuroHYP) (2010). Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J. Cereb. Blood Flow Metab. 30, 1079–1093.10.1038/jcbfm.2010.44Search in Google Scholar PubMed PubMed Central

van der Worp, H.B., Macleod, M.R., Bath, P.M.W., Demotes, J., Durand-Zaleski, I., Gebhardt, B., Gluud, C., Kollmar, R., Krieger, D.W., Lees, K.R., et al. (2014). EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke. Int. J. Stroke 9, 642–645.10.1111/ijs.12294Search in Google Scholar PubMed

Veterinary Information Network (VIN) – For Veterinarians, By Veterinarians.Search in Google Scholar

Virley, D. (2005). Choice, Methodology, and Characterization of Focal Ischemic Stroke Models. In: Stroke Genomics. Methods in Molecular Medicine. S.J. Read and Virley D, eds. (Totowa, NJ, USA: Humana Press), vol 104, pp. 19–48.Search in Google Scholar

Wang, R.-Y., Wang, P.S.-G., and Yang, Y.-R. (2003). Effect of age in rats following middle cerebral artery occlusion. Gerontology 49, 27–32.10.1159/000066505Search in Google Scholar PubMed

Wang, S.H., Zhang, Z., Guo, Y.J., Zhou, H., Teng, G.J., and Chen, B.A. (2009). Anhedonia and activity deficits in rats: impact of post-stroke depression. J. Psychopharmacol. Oxf. Engl. 23, 295–304.10.1177/0269881108089814Search in Google Scholar PubMed

Wilcox, J.T., Semple, E., Gartley, C., Brisson, B.A., Perrault, S.D., Villagómez, D.A.F., Tayade, C., Becker, S., Lanza, R., and Betts, D.H. (2009). Characterization of canine embryonic stem cell lines derived from different niche microenvironments. Stem Cells Dev. 18, 1167–1178.10.1089/scd.2008.0336Search in Google Scholar PubMed

Wilcox, J.T., Lai, J.K.Y., Semple, E., Brisson, B.A., Gartley, C., Armstrong, J.N., and Betts, D.H. (2011). Synaptically-competent neurons derived from canine embryonic stem cells by lineage selection with EGF and Noggin. PloS One 6, e19768.10.1371/journal.pone.0019768Search in Google Scholar PubMed PubMed Central

Windle, V., Szymanska, A., Granter-Button, S., White, C., Buist, R., Peeling, J., and Corbett, D. (2006). An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat. Exp. Neurol. 201, 324–334.10.1016/j.expneurol.2006.04.012Search in Google Scholar PubMed

Woodruff, T.M., Thundyil, J., Tang, S.-C., Sobey, C.G., Taylor, S.M., and Arumugam, T.V. (2011). Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener 6, 11.10.1186/1750-1326-6-11Search in Google Scholar PubMed PubMed Central

Wu, M.-H., Chio, C.-C., Tsai, K.-J., Chang, C.-P., Lin, N.-K., Huang, C.-C., and Lin, M.-T. (2016). Obesity exacerbates rat cerebral ischemic injury through enhancing ischemic adiponectin-containing neuronal apoptosis. Mol. Neurobiol. 53, 3702–3713.10.1007/s12035-015-9305-0Search in Google Scholar PubMed

Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K., and Masaki, T. (1988). A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332, 411–415.10.1038/332411a0Search in Google Scholar PubMed

Yang, L., Zhang, Z., Sun, D., Xu, Z., Yuan, Y., Zhang, X., and Li, L. (2011). Low serum BDNF may indicate the development of PSD in patients with acute ischemic stroke. Int. J. Geriatr. Psychiatry 26, 495–502.10.1002/gps.2552Search in Google Scholar PubMed

Yuan, J. (2009). Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis Int. J. Program. Cell Death 14, 469–477.10.1007/s10495-008-0304-8Search in Google Scholar PubMed PubMed Central

Zhang, Y., Jin, M., Du, B., Lin, H., Xu, C., Jiang, W., and Jia, J. (2015). A novel canine model of acute vertebral artery occlusion. PLoS One 10, e0142251.10.1371/journal.pone.0142251Search in Google Scholar PubMed PubMed Central

Zivin, J.A., Fisher, M., DeGirolami, U., Hemenway, C.C., and Stashak, J.A. (1985). Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science 230, 1289–1292.10.1126/science.3934754Search in Google Scholar PubMed

Zu, Q.-Q., Liu, S., Xu, X.-Q., Lu, S.-S., Sun, L., and Shi, H.-B. (2013). An endovascular canine stroke model: middle cerebral artery occlusion with autologous clots followed by ipsilateral internal carotid artery blockade. Lab. Invest. 93, 760–767.10.1038/labinvest.2013.65Search in Google Scholar PubMed

Received: 2017-08-30
Accepted: 2017-11-26
Published Online: 2018-02-05
Published in Print: 2018-08-28

©2018 Walter de Gruyter GmbH, Berlin/Boston

Scroll Up Arrow