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Translational Stroke Research
Published in: Translational Stroke Research 5/2019

Open Access 01-10-2019 | Original Article

Preclinical Validation of the Therapeutic Potential of Glasgow Oxygen Level Dependent (GOLD) Technology: a Theranostic for Acute Stroke

Authors: Graeme A. Deuchar, Josie C. van Kralingen, Lorraine M. Work, Celestine Santosh, Keith W. Muir, Chris McCabe, I. Mhairi Macrae

Published in: Translational Stroke Research | Issue 5/2019

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Abstract

In acute stroke patients, penumbral tissue is non-functioning but potentially salvageable within a time window of variable duration and represents target tissue for rescue. Reperfusion by thrombolysis and/or thrombectomy can rescue penumbra and improve stroke outcomes, but these treatments are currently available to a minority of patients. In addition to the utility of Glasgow Oxygen Level Dependent (GOLD) as an MRI contrast capable of detecting penumbra, its constituent perfluorocarbon (PFC) oxygen carrier, combined with normobaric hyperoxia, also represents a potential acute stroke treatment through improved oxygen delivery to penumbra. Preclinical studies were designed to test the efficacy of an intravenous oxygen carrier, the perfluorocarbon emulsion Oxycyte® (O-PFC), combined with normobaric hyperoxia (50% O2) in both in vitro (neuronal cell culture) and in vivo rat models of ischaemic stroke. Outcome was assessed through the quantification of lipid peroxidation and oxidative stress levels, mortality, infarct volume, neurological scoring and sensorimotor tests of functional outcome in two in vivo models of stroke. Additionally, we investigated evidence for any positive or negative interactions with the thrombolytic recombinant tissue plasminogen activator (rt-PA) following embolus-induced stroke in rats. Treatment with intravenous O-PFC + normobaric hyperoxia (50% O2) provided evidence of reduced infarct size and improved functional recovery. It did not exacerbate oxidative stress and showed no adverse interactions with rt-PA. The positive results and lack of adverse effects support human trials of O-PFC + 50% O2 normobaric hyperoxia as a potential therapeutic approach. Combined with the diagnostic data presented in the preceding paper, O-PFC and normobaric hyperoxia is a potential theranostic for acute ischaemic stroke.
Literature
1.
2.
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–7.CrossRef
3.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017–25.CrossRefPubMed
4.
Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384:1929–35.CrossRefPubMedPubMedCentral
5.
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–30.CrossRefPubMed
6.
Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018. [Epub ahead of print];379:611–22.CrossRefPubMed
7.
Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11–21.CrossRefPubMed
8.
Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708–18.CrossRefPubMedPubMedCentral
9.
Saver JL, Goyal M, van der Lugt A, Menon BK, Majoie CBLM, Dippel DW, et al. Time to treatment with endovascular thrombectomy and outcomes from ischaemic stroke: a meta-analysis. JAMA. 2016;316:1279–88.CrossRefPubMed
10.
Wheeler HM, Mlynash M, Inoue M, Tipirnini A, Liggins J, Bammer R, et al. The growth rate of early DWI lesions is highly variable and associated with penumbral salvage and clinical outcomes following endovascular reperfusion. Int J Stroke. 2015;10:723–9.CrossRefPubMedPubMedCentral
11.
Clark LC Jr, Becattini F, Kaplan S. The physiological effects of artificial blood made from inert organic oxygen solvents. Ala J Med Sci. 1972;9:16–29.PubMed
12.
Spiess BD. Perfluorocarbon emulsions as a promising technology: a review of tissue and vascular gas dynamics. J Appl Physiol. 1985;106:1444–52.CrossRef
13.
14.
Deuchar GA, Brennan D, Holmes WM, et al. Perfluorocarbon enhanced Glasgow Oxygen Level Dependent (GOLD) magnetic resonance metabolic imaging identifies the penumbra following acute ischemic stroke. Theranostics. 2018;12:1706–22.CrossRef
15.
Santosh C, Brennan D, McCabe C, et al. Potential use of Oxygen as a metabolic bio-tracer in combination with T2* weighted MRI, to define the ischemic penumbra. J CBF & Metabol. 2008;28:1742–53.
16.
Dani KA, Santosh C, Brennan D, McCabe C, Holmes WM, Condon B, et al. T2* weighted magnetic resonance imaging with hyperoxia in acute ischemic stroke. Ann Neurol. 2010;68:37–47.CrossRefPubMed
17.
Robertson C, McCabe C, Gallagher L, et al. Stroke penumbra defined by an MRI-based oxygen challenge technique: 1. Validation using [14C]2-deoxyglucose autoradiography. J CBF & Metabol. 2011;31:1778–87.
18.
Robertson C, McCabe C, Gallagher L, et al. Stroke penumbra defined by an MRI-based oxygen challenge technique: 2. Validation based on the consequences of reperfusion. J CBF & Metabol. 2011;31:1788–98.
19.
Deuchar GA, Brennan D, Griffiths H, et al. Perflourocarbons enhance a T2* based MRI technique for identifying the penumbra in a rat model of acute ischemic stroke. J CBF & Metabol. 2013;33:1422–8.
20.
Robertson CA, McCabe C, Lopez-Gonzalez MR, Deuchar GA, Dani K, Holmes WM, et al. Detection of ischemic penumbra using combined perfusion and T2* oxygen challenge imaging. Int J Stroke. 2015;10:42–50.CrossRefPubMed
21.
Dani KA, Moreton FC, Santosh C, et al. Oxygen challenge MR imaging in healthy human volunteers. J CBF & Metabol. 2017;37:366–76.
22.
Daugherty WP, Levasseur JE, Sun D, Spiess BD, Bullock MR. Perfluorocarbon emulsion improves cerebral oxygenation and mitochondrial function after fluid percussion brain injury in rats. Neurosurgery. 2004;54:1223–30.CrossRefPubMed
23.
Kwon TH, Sun D, Daugherty WP, Spiess BD, Bullock MR. Effect of perfluorocarbons on brain oxygenation and ischemic damage in an acute subdural hematoma model in rats. J Neurosurg. 2005;103:724–30.CrossRefPubMed
24.
Cabrales P, Carlos Briceno J. Delaying blood transfusion in experimental acute anemia with a perfluorocarbon emulsion. Anesthesiology. 2011;114:901–11.CrossRefPubMed
25.
Yang ZJ, Price CD, Bosco G, Tucci M, el-Badri NS, Mangar D, et al. The effect of isovolemic hemodilution with oxycyte, a perfluorocarbon emulsion, on cerebral blood flow in rats. PLoS One. 2008;3:e2010.CrossRefPubMedPubMedCentral
26.
Woitzik J, Weinzierl N, Schilling L. Early administration of a second-generation perfluorochemical decreases ischemic brain damage in a model of permanent middle cerebral artery occlusion in the rat. Neurol Res. 2005;27:509–15.CrossRefPubMed
27.
Eckmann DM, Armstead SC. Surfactant reduction of cerebral infarct size and behavioral deficit in a rat model of cerebrovascular arterial gas embolism. J Appl Physiol. 2013;115:868–76.CrossRefPubMedPubMedCentral
28.
Zhou Z, Sun D, Levasseur JE, Merenda A, Hamm RJ, Zhu J, et al. Perfluorocarbon emulsions improve cognitive recovery after lateral fluid percussion brain injury in rats. Neurosurgery. 2008;63:799–806.CrossRefPubMed
29.
Schroeder JL, Highsmith JM, Young HF, Mathern BE. Reduction of hypoxia by perfluorocarbon emulsion in a traumatic spinal cord injury model. J Neurosurg Spine. 2008;9:213–20.CrossRefPubMed
30.
Yacoub A, Hajec MC, Stanger R, Wan W, Young H, Mathern BE. Neuroprotective effects of perflurocarbon (oxycyte) after contusive spinal cord injury. J Neurotrauma. 2014;31:256–67.CrossRefPubMedPubMedCentral
31.
32.
Garcia JH, Wagner S, Liu KF, Hu XJ. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke. 1995;26:627–35.CrossRefPubMed
33.
Bouet V, Boulouard M, Toutain J, Divoux D, Bernaudin M, Schumann-Bard P, et al. The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice. Nat Protoc. 2009;4:1560–4.CrossRefPubMed
34.
Lo EH, Pierce AR, Mandeville JB, Rosen BR. Neuroprotection with NBQX in rat focal cerebral ischemia. Effects on ADC probability distribution functions and diffusion–perfusion relationships. Stroke. 1997;28:439–47.CrossRefPubMed
35.
Gerriets T, Stolz E, Walberer M, Müller C, Kluge A, Bachmann A, et al. Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging. Stroke. 2004;35:566–71.CrossRefPubMed
36.
Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab. 1990;10:290–3.CrossRefPubMed
37.
Tawil SE, Muir KW. Thrombolysis and thrombectomy for acute ischaemic stroke. Clin Med. 2017;17:161–5.CrossRef
38.
Back T. Pathophysiology of the ischemic penumbra—revision of a concept. Cell Mol Neurobiol. 1998;18:621–38.CrossRefPubMed
39.
Ford DH, Systems LABB. Elsevier, Amsterdam. 1968:p275.
40.
Schneider UC, Karutz T, Schilling L, Woitzik J. Administration of a second generation perfluorochemical in combination with hyperbaric oxygenation does not provide additional benefit in a model of permanent middle cerebral artery occlusion in rats. Springerplus. 2014;3:32–7.CrossRefPubMedPubMedCentral
41.
Brown AT, Arthur MC, Nix JS, Montgomery JA, Skinner RD, Roberson PK, et al. Dodecafluoropentane emulsion (DDFPe) decreases stroke size and improves neurological scores in a permanent occlusion rat stroke model. Open Neurol J. 2014;8:27–33.CrossRefPubMedPubMedCentral
42.
43.
Woods SD, Skinner RD, Ricca AM, Brown AT, Lowery JD, Borrelli MJ, et al. Progress in dodecafluoropentane emulsion as a neuroprotective agent in a rabbit stroke model. Mol Neurobiol. 2013;48:363–7.CrossRefPubMedPubMedCentral
44.
Culp WC, Brown AT, Lowery JD, Arthur MC, Roberson PK, Skinner RD. Dodecafluoropentane emulsion extends window for tPA therapy in a rabbit stroke model. Mol Neurobiol. 2015;52:979–84.CrossRefPubMedPubMedCentral
45.
46.
Weaver J, Liu KJ. Does normobaric hyperoxia increase oxidative stress in acute ischemic stroke? A critical review of the literature. Med Gas Res. 2015;5:11.CrossRefPubMedPubMedCentral
47.
Hakimelahi R, Vachha BA, Copen WA, Papini GDE, He J, Higazi MM, et al. Time and diffusion lesion size in major anterior circulation ischemic strokes. Stroke. 2014;45:2936–41.CrossRefPubMed
Metadata
Title
Preclinical Validation of the Therapeutic Potential of Glasgow Oxygen Level Dependent (GOLD) Technology: a Theranostic for Acute Stroke
Authors
Graeme A. Deuchar
Josie C. van Kralingen
Lorraine M. Work
Celestine Santosh
Keith W. Muir
Chris McCabe
I. Mhairi Macrae
Publication date
01-10-2019
Publisher
Springer US
Published in
Translational Stroke Research / Issue 5/2019
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-018-0679-y

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