Abstract
An argument for preclinical stroke research to make more use of the permanent middle cerebral artery occlusion (MCAO) model, rather than transient MCAO, is presented. Despite STAIR recommending permanent MCAO as the primary model, preclinical stroke research has not been listened. In 2012, Hossmann reported that 64% of the treatment studies for MCAO used prompt transient MCAO models and only 36% of the studies used permanent MCAO or gradual transient MCAO (i.e., embolic stroke model). Then, in 2014 and 2015, 88% of published basic science studies on large vessel occlusion used the transient MCAO model. However, this model only represents 2.5–11.3% of large vessel stroke patients. Therefore, the transient MCAO model, which mimics stroke with reperfusion, does not accurately reflect the majority of clinical stroke cases. Thus, once again, the argument for studying permanent MCAO as a primary model is made and supported.
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References
Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30(12):2752–8.
Hossmann K-A. Cerebral ischemia: models, methods and outcomes. Neuropharmacology. 2008;55(3):257–70.
Hossmann KA. The two pathophysiologies of focal brain ischemia: implications for translational stroke research. J Cereb Blood Flow Metabol. 2012;32(7):1310–6. doi:10.1038/jcbfm.2011.186.
Kahle MP, Bix GJ. Successfully climbing the “STAIRs”: surmounting failed translation of experimental ischemic stroke treatments. Stroke Res Treat. 2012;2012:374098.
Rai AT. Red pill, blue pill: reflections on the emerging large vessel stroke ‘market’. J Neurointerventional Surg. 2015;7(9):623–5.
Gonzalez RG, Furie KL, Goldmacher GV, Smith WS, Kamalian S, Payabvash S, et al. Good outcome rate of 35% in IV-tPA-treated patients with computed tomography angiography confirmed severe anterior circulation occlusive stroke. Stroke. 2013;44(11):3109–13.
Meyers PM, Schumacher HC, Connolly ES Jr, Heyer EJ, Gray WA, Higashida RT. Current status of endovascular stroke treatment. Circulation. 2011;123(22):2591–601.
Wiacek M, Kaczorowski R, Homa J, Filip E, Darocha J, Dudek D, et al. Single-center experience of stent retriever thrombectomy in acute ischemic stroke. Neurol Neurochir Polska. 2017;51(1):12–8.
Yoshimura S, Sakai N, Okada Y, Kitagawa K, Kimura K, Tanahashi N, et al. Efficacy of endovascular treatment for acute cerebral large-vessel occlusion: analysis of nationwide prospective registry. J Stroke Cerebrovasc Dis. 2014;23(5):1183–90.
Saver JL. Improving reperfusion therapy for acute ischaemic stroke. J Thromb Haemostasis. 2011;9(Suppl 1):333–43.
Cloft HJ, Rabinstein A, Lanzino G, Kallmes DF. Intra-arterial stroke therapy: an assessment of demand and available work force. Am J Neuroradiol. 2009;30(3):453–8.
Chen CJ, Ding D, Starke RM, Mehndiratta P, Crowley RW, Liu KC, et al. Endovascular vs medical management of acute ischemic stroke. Neurology. 2015;85(22):1980–90.
Gasparotti R, Grassi M, Mardighian D, Frigerio M, Pavia M, Liserre R, et al. Perfusion CT in patients with acute ischemic stroke treated with intra-arterial thrombolysis: predictive value of infarct core size on clinical outcome. Am J Neuroradiol. 2009;30(4):722–7.
Saver JL, Johnston KC, Homer D, Wityk R, Koroshetz W, Truskowski LL, et al. Infarct volume as a surrogate or auxiliary outcome measure in ischemic stroke clinical trials. The RANTTAS Investig Stroke. 1999;30(2):293–8.
Timpone VM, Lev MH, Kamalian S, Morais LT, Franceschi AM, Souza L, et al. Percentage insula ribbon infarction of >50% identifies patients likely to have poor clinical outcome despite small DWI infarct volume. Am J Neuroradiol. 2015;36(1):40–5.
Man S, Aoki J, Hussain MS, Wisco D, Tateishi Y, Toth G, et al. Predictors of infarct growth after endovascular therapy for acute ischemic stroke. J Stroke Cerebrovasc Dis. 2015;24(2):401–7.
Smith WS, Lev MH, English JD, Camargo EC, Chou M, Johnston SC, et al. Significance of large vessel intracranial occlusion causing acute ischemic stroke and TIA. Stroke. 2009;40(12):3834–40.
Investigators TNSS. Recombinant tissue plasminogen activator for minor strokes: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study experience. Ann Emerg Med. 2005;46:243–52.
Aiyagari V, Diringer MN. Management of large hemispheric strokes in the neurological intensive care unit. Neurologist. 2002;8(3):152–62.
Bang OY, Saver JL, Kim SJ, Kim GM, Chung CS, Ovbiagele B, et al. Collateral flow averts hemorrhagic transformation after endovascular therapy for acute ischemic stroke. Stroke. 2011;42(8):2235–9.
Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38(3):967–73.
Heinsius T, Bogousslavsky J, Van Melle G. Large infarcts in the middle cerebral artery territory. Etiology and outcome patterns. Neurology. 1998;50(2):341–50.
Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol. 1996;53(4):309–15.
Rieke K, Schwab S, Krieger D, von Kummer R, Aschoff A, Schuchardt V, et al. Decompressive surgery in space-occupying hemispheric infarction: results of an open, prospective trial. Crit Care Med. 1995;23(9):1576–87.
DAWN trial results demonstrate a 73% reduction in disability in stroke patients treated up to 24 hours. 2017. http://www.prweb.com/releases/2017/05/prweb14339427.htm. Accessed May 22, 2017 2017.
Stem cell therapies as an emerging paradigm in stroke (STEPS). bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke. 2009;40(2):510–5.
Lapchak PA, Zhang JH, Noble-Haeusslein LJ. RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Trans Stroke Res. 2013;4(3):279–85.
Ahnstedt H, McCullough LD, Cipolla MJ. The importance of considering sex differences in translational stroke research. Trans Stroke Res. 2016;7(4):261–73.
Boltze J, Ayata C. Challenges and controversies in translational stroke research—an introduction. Transl Stroke Res. 2016;7(5):355–7.
Boltze J, Wagner D-C, Henninger N, Plesnila N, Ayata C. Phase III preclinical trials in translational stroke research: community response on framework and guidelines. Transl Stroke Res. 2016;7(4):241–7.
Ergul A, Hafez S, Fouda A, Fagan SC. Impact of comorbidities on acute injury and recovery in preclinical stroke research: focus on hypertension and diabetes. Transl Stroke Res. 2016;7(4):248–60.
Kent TA, Mandava P. Embracing biological and methodological variance in a new approach to pre-clinical stroke testing. Transl Stroke Res. 2016;7(4):274–83.
Braeuninger S, Kleinschnitz C. Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems. Exp Transl Stroke Med. 2009;1(1):8.
Fluri F, Schuhmann MK, Kleinschnitz C. Animal models of ischemic stroke and their application in clinical research. Drug Design, Development and Therapy. 2015;9:3445–54.
Ginsberg MD, Busto R. Rodent models of cerebral ischemia. Stroke. 1989;20(12):1627–42.
Sicard KM, Fisher M. Animal models of focal brain ischemia. Exp Transl Stroke Med. 2009;1(1):7.
Nour M, Scalzo F, Liebeskind DS. Ischemia-reperfusion injury in stroke. Interventional Neurol. 2013;1(3–4):185–99.
Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J. Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology. 2007;49(2):93–102.
Li P, Murphy TH. Two-photon imaging during prolonged middle cerebral artery occlusion in mice reveals recovery of dendritic structure after reperfusion. J Neurosci. 2008;28(46):11970–9.
Liu S, Levine SR, Winn HR. Targeting ischemic penumbra: part I—from pathophysiology to therapeutic strategy. J Exp Stroke Transl Med. 2010;3(1):47–55.
Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79(4):1431–568.
Pu H, Jiang X, Hu X, Xia J, Hong D, Zhang W, et al. Delayed docosahexaenoic acid treatment combined with dietary supplementation of omega-3 fatty acids promotes long-term neurovascular restoration after ischemic stroke. Transl Stroke Res. 2016;7(6):521–34.
Terada T, Yamaga H, Tsumoto T, Masuo O, Itakura T. Use of an embolic protection system during endovascular recanalization of a totally occluded cervical internal carotid artery at the chronic stage. Case report J Neurosurg. 2005;102(3):558–64.
Yu W, Kostanian V, Fisher M. Endovascular recanalization of basilar artery occlusion 80 days after symptom onset. Stroke. 2007;38(4):1387–9.
Henninger N, Fisher M. Extending the time window for endovascular and pharmacological reperfusion. Transl Stroke Res. 2016;7(4):284–93.
Cai W, Zhu Y, Furuya K, Li Z, Sokabe M, Chen L. Two different molecular mechanisms underlying progesterone neuroprotection against ischemic brain damage. Neuropharmacology. 2008;55(2):127–38.
Charles MS, Drunalini Perera PN, Doycheva DM, Tang J. Granulocyte-colony stimulating factor activates JAK2/PI3K/PDE3B pathway to inhibit corticosterone synthesis in a neonatal hypoxic-ischemic brain injury rat model. Exp Neurol. 2015;272:152–9.
Hasegawa Y, Suzuki H, Altay O, Rolland W, Zhang JH. Role of the sphingosine metabolism pathway on neurons against experimental cerebral ischemia in rats. Transl Stroke Res. 2013;4(5):524–32.
Hasegawa Y, Suzuki H, Sozen T, Rolland W, Zhang JH. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke. 2010;41(2):368–74.
Kraft P, Gob E, Schuhmann MK, Gobel K, Deppermann C, Thielmann I, et al. FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotection. Stroke. 2013;44(11):3202–10.
Li L, Klebe D, Doycheva D, McBride DW, Krafft PR, Flores J, et al. G-CSF ameliorates neuronal apoptosis through GSK-3beta inhibition in neonatal hypoxia-ischemia in rats. Exp Neurol. 2015;263:141–9.
Li L, McBride DW, Doycheva D, Dixon BJ, Krafft PR, Zhang JH, et al. G-CSF attenuates neuroinflammation and stabilizes the blood-brain barrier via the PI3K/Akt/GSK-3beta signaling pathway following neonatal hypoxia-ischemia in rats. Exp Neurol. 2015;272:135–44.
Liesz A, Sun L, Zhou W, Schwarting S, Mracsko E, Zorn M, et al. FTY720 reduces post-ischemic brain lymphocyte influx but does not improve outcome in permanent murine cerebral ischemia. PLoS One. 2011;6(6):e21312.
Nazari M, Keshavarz S, Rafati A, Namavar MR, Haghani M. Fingolimod (FTY720) improves hippocampal synaptic plasticity and memory deficit in rats following focal cerebral ischemia. Brain Res Bull. 2016;124:95–102.
Shi X, Doycheva DM, Xu L, Tang J, Yan M, Zhang JH. Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats. Neurobiol Dis. 2016;95:111–21.
Shi X, Xu L, Doycheva DM, Tang J, Yan M, Zhang JH. Sestrin2, as a negative feedback regulator of mTOR, provides neuroprotection by activation AMPK phosphorylation in neonatal hypoxic-ischemic encephalopathy in rat pups. J Cereb Blood Flow Metabol. 2016;
Wei H, Li Y, Han S, Liu S, Zhang N, Zhao L, et al. cPKCγ-modulated autophagy in neurons alleviates ischemic injury in brain of mice with ischemic stroke through Akt-mTOR pathway. Transl Stroke Res. 2016;7(6):497–511.
Yao Y, Miao W, Liu Z, Han W, Shi K, Shen Y, et al. Dimethyl fumarate and monomethyl fumarate promote post-ischemic recovery in mice. Transl Stroke Res. 2016;7(6):535–47.
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Devin McBride was partially supported by the National Institutes of Health F32 Fellowship (1F32HL136193, DWM).
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McBride, D.W., Zhang, J.H. Precision Stroke Animal Models: the Permanent MCAO Model Should Be the Primary Model, Not Transient MCAO. Transl. Stroke Res. 8, 397–404 (2017). https://doi.org/10.1007/s12975-017-0554-2
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DOI: https://doi.org/10.1007/s12975-017-0554-2