159
Views
40
CrossRef citations to date
0
Altmetric
Perspective

Translating promising preclinical neuroprotective therapies to human stroke trials

&
Pages 433-449 | Published online: 10 Jan 2014

References

  • Lloyd-Jones D, Adams RJ, Brown TM et al. Heart disease and stroke statistics – 2010 update: a report from the American Heart Association. Circulation121(7), e46–e215 (2010).
  • Zorowitz RD, Chen E, Tong KB, Laouri M. Costs and rehabilitation use of stroke survivors: a retrospective study of Medicare beneficiaries. Top Stroke Rehabil.16(5), 309–320 (2009).
  • Kidwell CS, Liebeskind DS, Starkman S, Saver JL. Trends in acute ischemic stroke trials through the 20th Century. Stroke32(6), 1349–1359 (2001).
  • Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke33(8), 2123–2136 (2002).
  • O’Collins VE, Macleod MR, Donnan GA, Horky LL, van Der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann. Neurol.59(3), 467–477 (2006).
  • Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx2(3), 396–409 (2005).
  • Fisher M, Finklestein S. Pharmacological approaches to stroke recovery. Cerebrovasc. Dis.9(Suppl. 5), 29–32 (1999).
  • Howells DW, Porritt MJ, Rewell SS et al. Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia. J. Cereb. Blood Flow Metab.30(8), 1412–1431 (2010).
  • Macleod MR, O’collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke35(5), 1203–1208 (2004).
  • STAIR. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke30(12), 2752–2758 (1999).
  • Fisher M, Feuerstein G, Howells DW et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke40(6), 2244–2250 (2009).
  • Maples KR, Green AR, Floyd RA. Nitrone-related therapeutics: potential of NXY-059 for the treatment of acute ischaemic stroke. CNS Drugs18(15), 1071–1084 (2004).
  • Hess DC. NXY-059: a hopeful sign in the treatment of stroke. Stroke37(10), 2649–2650 (2006).
  • Marshall JW, Ridley RM. Assessment of cognitive and motor deficits in a marmoset model of stroke. ILAR J.44(2), 153–160 (2003).
  • Marshall JW, Ridley RM, Baker HF, Hall LD, Carpenter TA, Wood NI. Serial MRI, functional recovery, and long-term infarct maturation in a non-human primate model of stroke. Brain Res. Bull.61(6), 577–585 (2003).
  • Marshall JW, Duffin KJ, Green AR, Ridley RM. NXY-059, a free radical – trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke32(1), 190–198 (2001).
  • Marshall JW, Cummings RM, Bowes LJ, Ridley RM, Green AR. Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke34(9), 2228–2233 (2003).
  • Marshall JW, Green AR, Ridley RM. Comparison of the neuroprotective effect of clomethiazole, AR-R15896AR and NXY-059 in a primate model of stroke using histological and behavioural measures. Brain Res.972(1–2), 119–126 (2003).
  • Lees KR, Zivin JA, Ashwood T et al. NXY-059 for acute ischemic stroke. N. Engl. J. Med.354(6), 588–600 (2006).
  • Shuaib A, Lees KR, Lyden P et al. NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med.357(6), 562–571 (2007).
  • Diener HC, Lees KR, Lyden P et al. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke39(6), 1751–1758 (2008).
  • Dirnagl U. Bench to bedside: the quest for quality in experimental stroke research. J. Cereb. Blood Flow Metab.26(12), 1465–1478 (2006).
  • Savitz SI, Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann. Neurol.61(5), 396–402 (2007).
  • Philip M, Benatar M, Fisher M, Savitz SI. Methodological quality of animal studies of neuroprotective agents currently in Phase II/III acute ischemic stroke trials. Stroke40(2), 577–581 (2009).
  • Savitz SI. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp. Neurol.205(1), 20–25 (2007).
  • Liu Y, Song XD, Liu W, Zhang TY, Zuo J. Glucose deprivation induces mitochondrial dysfunction and oxidative stress in PC12 cell line. J. Cell Mol. Med.7(1), 49–56 (2003).
  • Behl C, Lezoualc’h F, Trapp T, Widmann M, Skutella T, Holsboer F. Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrinology138(1), 101–106 (1997).
  • Booher J, Sensenbrenner M. Growth and cultivation of dissociated neurons and glial cells from embryonic chick, rat and human brain in flask cultures. Neurobiology2(3), 97–105 (1972).
  • Goldberg MP, Choi DW. Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J. Neurosci.13(8), 3510–3524 (1993).
  • Newell DW, Barth A, Papermaster V, Malouf AT. Glutamate and non-glutamate receptor mediated toxicity caused by oxygen and glucose deprivation in organotypic hippocampal cultures. J. Neurosci.15(11), 7702–7711 (1995).
  • Strasser U, Fischer G. Quantitative measurement of neuronal degeneration in organotypic hippocampal cultures after combined oxygen/glucose deprivation. J. Neurosci. Methods57(2), 177–186 (1995).
  • Taylor CP, Weber ML, Gaughan CL, Lehning EJ, Lopachin RM. Oxygen/glucose deprivation in hippocampal slices: altered intraneuronal elemental composition predicts structural and functional damage. J. Neurosci.19(2), 619–629 (1999).
  • Bacigaluppi M, Comi G, Hermann DM. Animal models of ischemic stroke. Part two: modeling cerebral ischemia. Open Neurol. J.4, 34–38 (2010).
  • Sundstrom L, Morrison B 3rd, Bradley M, Pringle A. Organotypic cultures as tools for functional screening in the CNS. Drug Discov. Today10(14), 993–1000 (2005).
  • Feuerstein GZ, Chavez J. Translational medicine for stroke drug discovery: the pharmaceutical industry perspective. Stroke40(Suppl. 3), S121–S125 (2009).
  • Mattson MP, Barger SW, Begley JG, Mark RJ. Calcium, free radicals, and excitotoxic neuronal death in primary cell culture. Methods Cell Biol.46, 187–216 (1995).
  • Li L, Prabhakaran K, Shou Y, Borowitz JL, Isom GE. Oxidative stress and cyclooxygenase-2 induction mediate cyanide-induced apoptosis of cortical cells. Toxicol. Appl. Pharmacol.185(1), 55–63 (2002).
  • Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch.460(2), 525–542 (2010).
  • Szydlowska K, Tymianski M. Calcium, ischemia and excitotoxicity. Cell Calcium47(2), 122–129 (2010).
  • Choi DW, Maulucci-Gedde M, Kriegstein AR. Glutamate neurotoxicity in cortical cell culture. J. Neurosci.7(2), 357–368 (1987).
  • Rose CR, Ransom BR. Mechanisms of H+ and Na+ changes induced by glutamate, kainate, and D-aspartate in rat hippocampal astrocytes. J. Neurosci.16(17), 5393–5404 (1996).
  • Jensen JB, Schousboe A, Pickering DS. AMPA receptor mediated excitotoxicity in neocortical neurons is developmentally regulated and dependent upon receptor desensitization. Neurochem. Int.32(5–6), 505–513 (1998).
  • Lau AC, Cui H, Tymianski M. The use of propidium iodide to assess excitotoxic neuronal death in primary mixed cortical cultures. Methods Mol. Biol.399, 15–29 (2007).
  • Liu Y, Peterson DA, Kimura H, Schubert D. Mechanism of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction J. Neurochem.69(2), 581–593 (1997).
  • Greene LA, Aletta JM, Rukenstein A, Green SH. PC12 pheochromocytoma cells: culture, nerve growth factor treatment, and experimental exploitation. Methods Enzymol.147, 207–216 (1987).
  • Choi DW. Ischemia-induced neuronal apoptosis. Curr. Opin. Neurobiol.6(5), 667–672 (1996).
  • Dugan LL, Sensi SL, Canzoniero LM et al. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J. Neurosci.15(10), 6377–6388 (1995).
  • Lee WH, Kang S, Vlachos PP, Lee YW. A novel in vitro ischemia/reperfusion injury model. Arch. Pharm. Res.32(3), 421–429 (2009).
  • Lok J, Gupta P, Guo S et al. Cell–cell signaling in the neurovascular unit. Neurochem. Res.32(12), 2032–2045 (2007).
  • Grant GA, Abbott NJ, Janigro D. Understanding the physiology of the blood-brain barrier: in vitro models. News Physiol. Sci.13, 287–293 (1998).
  • Balbuena P, Li W, Magnin-Bissel G, Meldrum JB, Ehrich M. Comparison of two blood–brain barrier in vitro systems: cytotoxicity and transfer assessments of malathion/oxon and lead acetate. Toxicol. Sci.114(2), 260–271 (2010).
  • Holopainen IE. Organotypic hippocampal slice cultures: a model system to study basic cellular and molecular mechanisms of neuronal cell death, neuroprotection, and synaptic plasticity. Neurochem. Res.30(12), 1521–1528 (2005).
  • Noraberg J, Poulsen FR, Blaabjerg M et al. Organotypic hippocampal slice cultures for studies of brain damage, neuroprotection and neurorepair. Curr. Drug Targets CNS Neurol. Disord.4(4), 435–452 (2005).
  • Yakovlev AG, Faden AI. Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRx1(1), 5–16 (2004).
  • Sapolsky RM. Neuroprotective gene therapy against acute neurological insults. Nat. Rev. Neurosci.4(1), 61–69 (2003).
  • Stieger K, Belbellaa B, Le Guiner C, Moullier P, Rolling F. In vivo gene regulation using tetracycline-regulatable systems. Adv. Drug Deliv. Rev.61(7–8), 527–541 (2009).
  • Cui H, Hayashi A, Sun HS et al. PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J. Neurosci.27(37), 9901–9915 (2007).
  • Culmsee C, Krieglstein J. Ischaemic brain damage after stroke: new insights into efficient therapeutic strategies. International Symposium on Neurodegeneration and Neuroprotection. EMBO Rep.8(2), 129–133 (2007).
  • Sattler R, Xiong Z, Lu WY, Hafner M, Macdonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science284(5421), 1845–1848 (1999).
  • Aarts M, Liu Y, Liu L et al. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science298(5594), 846–850 (2002).
  • Braeuninger S, Kleinschnitz C. Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems. Exp. Transl. Stroke Med.1, 8 (2009).
  • Jonas S, Aiyagari V, Vieira D, Figueroa M. The failure of neuronal protective agents versus the success of thrombolysis in the treatment of ischemic stroke. The predictive value of animal models. Ann. NY Acad. Sci.939, 257–267 (2001).
  • Cramer SC. Clinical issues in animal models of stroke and rehabilitation. ILAR J.44(2), 83–84 (2003).
  • Hunter AJ, Green AR, Cross AJ. Animal models of acute ischaemic stroke: can they predict clinically successful neuroprotective drugs? Trends Pharmacol. Sci.16(4), 123–128 (1995).
  • Curry SH. Why have so many drugs with stellar results in laboratory stroke models failed in clinical trials? A theory based on allometric relationships. Ann. NY Acad. Sci.993, 69–74; discussion 79–81 (2003).
  • Bacigaluppi M, Comi G, Hermann DM. Animal models of ischemic stroke. Part one: modeling risk factors. Open Neurol. J.4, 26–33 (2010).
  • Hoyte L, Kaur J, Buchan AM. Lost in translation: taking neuroprotection from animal models to clinical trials. Exp. Neurol.188(2), 200–204 (2004).
  • Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: lessons from animal models. Metab. Brain Dis.19(3–4), 151–167 (2004).
  • Fukuda S, Del Zoppo GJ. Models of focal cerebral ischemia in the nonhuman primate. ILAR J.44(2), 96–104 (2003).
  • Bihel E, Pro-Sistiaga P, Letourneur A et al. Permanent or transient chronic ischemic stroke in the non-human primate: behavioral, neuroimaging, histological, and immunohistochemical investigations. J. Cereb. Blood Flow Metab.30(2), 273–285 (2010).
  • 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. Stroke17(3), 472–476 (1986).
  • Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke20(1), 84–91 (1989).
  • 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.182(2), 261–274 (2003).
  • Peeling J, Corbett D, Del Bigio MR, Hudzik TJ, Campbell TM, Palmer GC. Rat middle cerebral artery occlusion: correlations between histopathology, T2-weighted magnetic resonance imaging, and behavioral indices. J. Stroke Cerebrovasc. Dis.10(4), 166–177 (2001).
  • Palmer GC, Peeling J, Corbett D, Del Bigio MR, Hudzik TJ. T2-weighted MRI correlates with long-term histopathology, neurology scores, and skilled motor behavior in a rat stroke model. Ann. NY Acad. Sci.939, 283–296 (2001).
  • Saver JL, Johnston KC, Homer D et al. Infarct volume as a surrogate or auxiliary outcome measure in ischemic stroke clinical trials. The RANTTAS Investigators. Stroke30(2), 293–298 (1999).
  • Schaar KL, Brenneman MM, Savitz SI. Functional assessments in the rodent stroke model. Exp. Transl. Stroke Med.2(1), 13 (2010).
  • Devries AC, Nelson RJ, Traystman RJ, Hurn PD. Cognitive and behavioral assessment in experimental stroke research: will it prove useful? Neurosci. Biobehav. Rev.25(4), 325–342 (2001).
  • Grabowski M, Brundin P, Johansson BB. Paw-reaching, sensorimotor, and rotational behavior after brain infarction in rats. Stroke24(6), 889–895 (1993).
  • Roof RL, Schielke GP, Ren X, Hall ED. A comparison of long-term functional outcome after 2 middle cerebral artery occlusion models in rats. Stroke32(11), 2648–2657 (2001).
  • Cheng YD, Al-Khoury L, Zivin JA. Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx1(1), 36–45 (2004).
  • Ginsberg MD, Busto R. Rodent models of cerebral ischemia. Stroke20(12), 1627–1642 (1989).
  • Corbett D, Thornhill J. Temperature modulation (hypothermic and hyperthermic conditions) and its influence on histological and behavioral outcomes following cerebral ischemia. Brain Pathol.10(1), 145–152 (2000).
  • Buchan A, Pulsinelli WA. Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J. Neurosci.10(1), 311–316 (1990).
  • Hainsworth AH, Markus HS. Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J. Cereb. Blood Flow Metab.28(12), 1877–1891 (2008).
  • Feuerstein GZ, Zaleska MM, Krams M et al. Missing steps in the STAIR case: a translational medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke. J. Cereb. Blood Flow Metab.28(1), 217–219 (2008).
  • Minnerup J, Wersching H, Diederich K et al. Methodological quality of preclinical stroke studies is not required for publication in high-impact journals. J. Cereb. Blood Flow Metab.30(9), 1619–1624 (2010).
  • Schmitz J, Roos C, Zischler H. Primate phylogeny: molecular evidence from retroposons. Cytogenet. Genome Res.108(1–3), 26–37 (2005).
  • Zaleska MM, Mercado ML, Chavez J, Feuerstein GZ, Pangalos MN, Wood A. The development of stroke therapeutics: promising mechanisms and translational challenges. Neuropharmacology56(2), 329–341 (2009).
  • Murphy SJ, Mccullough LD, Smith JM. Stroke in the female: role of biological sex and estrogen. ILAR J.45(2), 147–159 (2004).
  • Graham SM, Mccullough LD, Murphy SJ. Animal models of ischemic stroke: balancing experimental aims and animal care. Comp. Med.54(5), 486–496 (2004).
  • Nehls DG, Cartwright M, Spetzler RF. Experimental primate stroke model. Neurosurgery18(3), 388–389 (1986).
  • Spetzler RF, Zabramski JM, Kaufman B, Yeung HN. Acute NMR changes during MCA occlusion: a preliminary study in primates. Stroke14(2), 185–191 (1983).
  • Mack WJ, Komotar RJ, Mocco J et al. Serial magnetic resonance imaging in experimental primate stroke: validation of MRI for pre-clinical cerebroprotective trials. Neurol. Res.25(8), 846–852 (2003).
  • Huang J, Mocco J, Choudhri TF et al. A modified transorbital baboon model of reperfused stroke. Stroke31(12), 3054–3063 (2000).
  • D’ambrosio AL, Sughrue ME, Mocco J et al. A modified transorbital baboon model of reperfused stroke. Methods Enzymol.386, 60–73 (2004).
  • Del Zoppo GJ, Copeland BR, Harker LA et al. Experimental acute thrombotic stroke in baboons. Stroke17(6), 1254–1265 (1986).
  • Mack WJ, King RG, Hoh DJ et al. An improved functional neurological examination for use in nonhuman primate studies of focal reperfused cerebral ischemia. Neurol. Res.25(3), 280–284 (2003).
  • Del Zoppo GJ, Copeland BR, Waltz TA, Zyroff J, Plow EF, Harker LA. The beneficial effect of intracarotid urokinase on acute stroke in a baboon model. Stroke17(4), 638–643 (1986).
  • Molina CA, Saver JL. Extending reperfusion therapy for acute ischemic stroke: emerging pharmacological, mechanical, and imaging strategies. Stroke36(10), 2311–2320 (2005).
  • Mocco J, Mack WJ, Ducruet AF et al. Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke. J. Neurosurg.105(4), 595–601 (2006).
  • Ducruet AF, Mocco J, Mack WJ et al. Pre-clinical evaluation of an sLe x-glycosylated complement inhibitory protein in a non-human primate model of reperfused stroke. J. Med. Primatol.36(6), 375–380 (2007).
  • Mocco J, Choudhri T, Huang J et al. HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ. Res.91(10), 907–914 (2002).
  • De Crespigny AJ, D’arceuil HE, Maynard KI et al. Acute studies of a new primate model of reversible middle cerebral artery occlusion. J. Stroke Cerebrovasc. Dis.14(2), 80–87 (2005).
  • Roitberg B, Khan N, Tuccar E et al. Chronic ischemic stroke model in cynomolgus monkeys: behavioral, neuroimaging and anatomical study. Neurol. Res.25(1), 68–78 (2003).
  • Murphy SJ, Kirsch JR, Zhang W et al. Can gender differences be evaluated in a rhesus macaque (Macaca mulatta) model of focal cerebral ischemia? Comp. Med.58(6), 588–596 (2008).
  • Takamatsu H, Tsukada H, Kakiuchi T, Nishiyama S, Noda A, Umemura K. Detection of reperfusion injury using PET in a monkey model of cerebral ischemia. J. Nucl. Med.41(8), 1409–1416 (2000).
  • West GA, Golshani KJ, Doyle KP et al. A new model of cortical stroke in the rhesus macaque. J. Cereb. Blood Flow Metab.29(6), 1175–1186 (2009).
  • Hirouchi Y, Suzuki E, Mitsuoka C et al. Neuroimaging and histopathological evaluation of delayed neurological damage produced by artificial occlusion of the middle cerebral artery in cynomolgus monkeys: establishment of a monkey model for delayed cerebral ischemia. Exp. Toxicol. Pathol.59(1), 9–16 (2007).
  • Maeda M, Takamatsu H, Furuichi Y et al. Characterization of a novel thrombotic middle cerebral artery occlusion model in monkeys that exhibits progressive hypoperfusion and robust cortical infarction. J. Neurosci. Methods146(1), 106–115 (2005).
  • Susumu T, Yoshikawa T, Akiyoshi Y, Nagata R, Fujiwara M, Kito G. Effects of intra-arterial urokinase on a non-human primate thromboembolic stroke model. J. Pharmacol. Sci.100(4), 278–284 (2006).
  • Furuichi Y, Katsuta K, Maeda M et al. Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy. Brain Res.965(1–2), 137–145 (2003).
  • Furuichi Y, Maeda M, Matsuoka N, Mutoh S, Yanagihara T. Therapeutic time window of tacrolimus (FK506) in a nonhuman primate stroke model: comparison with tissue plasminogen activator. Exp. Neurol.204(1), 138–146 (2007).
  • Takamatsu H, Tsukada H, Noda A et al. FK506 attenuates early ischemic neuronal death in a monkey model of stroke. J. Nucl. Med.42(12), 1833–1840 (2001).
  • Yoshikawa T, Akiyoshi Y, Susumu T et al. Ginsenoside Rb1 reduces neurodegeneration in the peri-infarct area of a thromboembolic stroke model in non-human primates. J. Pharmacol. Sci.107(1), 32–40 (2008).
  • Li HL, Yan C, Li J et al. Seroprevalence of Toxoplasma gondii in bred cynomolgus monkeys (Macaca fascicularis) in China. J. Parasitol.96(4), 807–808 (2010).
  • Kawaguchi AT, Haida M, Yamano M, Fukumoto D, Ogata Y, Tsukada H. Liposome-encapsulated hemoglobin ameliorates ischemic stroke in nonhuman primates: an acute study. J. Pharmacol. Exp. Ther.332(2), 429–436 (2010).
  • Zerhouni EA. Translational research: moving discovery to practice. Clin. Pharmacol. Ther.81(1), 126–128 (2007).
  • Woolf SH. The meaning of translational research and why it matters. JAMA299(2), 211–213 (2008).
  • Mandava P, Kalkonde YV, Rochat RH, Kent TA. A matching algorithm to address imbalances in study populations: application to the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator Acute Stroke Trial. Stroke41(4), 765–770 (2010).
  • Uyttenboogaart M, Stewart RE, Vroomen PC, De Keyser J, Luijckx GJ. Optimizing cutoff scores for the Barthel index and the modified Rankin scale for defining outcome in acute stroke trials. Stroke36(9), 1984–1987 (2005).
  • Muir KW. Heterogeneity of stroke pathophysiology and neuroprotective clinical trial design. Stroke33(6), 1545–1550 (2002).
  • Crossley NA, Sena E, Goehler J et al. Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach. Stroke39(3), 929–934 (2008).
  • Johnston K. What are surrogate outcome measures and why do they fail in clinical research? Neuroepidemiology18(4), 167–173 (1999).
  • Hoehn-Berlage M, Eis M, Back T, Kohno K, Yamashita K. Changes of relaxation times (T1, T2) and apparent diffusion coefficient after permanent middle cerebral artery occlusion in the rat: temporal evolution, regional extent, and comparison with histology. Magn. Reson. Med.34(6), 824–834 (1995).
  • Jokivarsi KT, Hiltunen Y, Tuunanen PI, Kauppinen RA, Grohn OH. Correlating tissue outcome with quantitative multiparametric MRI of acute cerebral ischemia in rats. J. Cereb. Blood Flow Metab.30(2), 415–427 (2010).
  • 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. Stroke17(6), 1304–1308 (1986).
  • Murakami Y, Takamatsu H, Noda A et al. Pharmacokinetic animal PET study of FK506 as a potent neuroprotective agent. J. Nucl. Med.45(11), 1946–1949 (2004).
  • Yanagihara T. Experimental stroke in gerbils: effect on translation and transcription. Brain Res.158(2), 435–444 (1978).
  • Kharlamov A, Laverde GC, Nemoto EM et al. MAP2 immunostaining in thick sections for early ischemic stroke infarct volume in non-human primate brain. J. Neurosci. Methods182(2), 205–210 (2009).
  • Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia – the ischemic penumbra. Stroke12(6), 723–725 (1981).
  • Ward KW, Smith BR. A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. II. Volume of distribution and mean residence time. Drug Metab. Dispos.32(6), 612–619 (2004).
  • Nudo RJ, Larson D, Plautz EJ, Friel KM, Barbay S, Frost SB. A squirrel monkey model of poststroke motor recovery. ILAR J.44(2), 161–174 (2003).
  • Yonas H, Wolfson SK Jr, Dujovny M, Boehnke M, Cook E. Selective lenticulostriate occlusion in the primate. A highly focal cerebral ischemia model. Stroke12(5), 567–572 (1981).
  • Hamberg LM, Hunter GJ, Maynard KI et al. Functional CT perfusion imaging in predicting the extent of cerebral infarction from a 3-hour middle cerebral arterial occlusion in a primate stroke model. AJNR Am. J. Neuroradiol.23(6), 1013–1021 (2002).
  • D’arceuil HE, Duggan M, He J, Pryor J, De Crespigny A. Middle cerebral artery occlusion in Macaca fascicularis: acute and chronic stroke evolution. J. Med. Primatol.35(2), 78–86 (2006).
  • Kito G, Nishimura A, Susumu T et al. Experimental thromboembolic stroke in cynomolgus monkey. J. Neurosci. Methods105(1), 45–53 (2001).
  • Kuge Y, Yokota C, Tagaya M et al. Serial changes in cerebral blood flow and flow-metabolism uncoupling in primates with acute thromboembolic stroke. J. Cereb. Blood Flow Metab.21(3), 202–210 (2001).
  • Qureshi AI, Suri MF, Ali Z et al. Intraarterial reteplase and intravenous abciximab for treatment of acute ischemic stroke. A preliminary feasibility and safety study in a non-human primate model. Neuroradiology47(11), 845–854 (2005).
  • Sughrue ME, Mocco J, Mack WJ et al. Bioethical considerations in translational research: primate stroke. Am. J. Bioeth.9(5), 3–12 (2009).
  • Dorman PJ, Sandercock PA. Considerations in the design of clinical trials of neuroprotective therapy in acute stroke. Stroke27(9), 1507–1515 (1996).
  • Fuster JM. Unit activity in prefrontal cortex during delayed-response performance: neuronal correlates of transient memory. J. Neurophysiol.36(1), 61–78 (1973).
  • Zola-Morgan S, Squire LR. Preserved learning in monkeys with medial temporal lesions: sparing of motor and cognitive skills. J. Neurosci.4(4), 1072–1085 (1984).
  • Palfi S, Conde F, Riche D et al. Fetal striatal allografts reverse cognitive deficits in a primate model of Huntington disease. Nat. Med.4(8), 963–966 (1998).
  • Herndon JG, Moss MB, Rosene DL, Killiany RJ. Patterns of cognitive decline in aged rhesus monkeys. Behav. Brain Res.87(1), 25–34 (1997).
  • Moore TL, Killiany RJ, Herndon JG, Rosene DL, Moss MB. Impairment in abstraction and set shifting in aged rhesus monkeys. Neurobiol. Aging24(1), 125–134 (2003).
  • Moss MB, Jonak E. Cerebrovascular disease and dementia: a primate model of hypertension and cognition. Alzheimers Dement.3(Suppl. 2), S6–S15 (2007).
  • Rother J. Neuroprotection does not work! Stroke39(2), 523–524 (2008).
  • Macleod MR, Fisher M, O’collins V et al. Good laboratory practice: preventing introduction of bias at the bench. Stroke40(3), e50–e52 (2009).
  • Zivin JA. Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA). Ann. Neurol.66(1), 6–10 (2009).
  • Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke40(7), 2438–2441 (2009).
  • Symon L, Crockard HA, Dorsch NW, Branston NM, Juhasz J. Local cerebral blood flow and vascular reactivity in a chronic stable stroke in baboons. Stroke6(5), 482–492 (1975).
  • Astrup J, Symon L, Branston NM, Lassen NA. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke8(1), 51–57 (1977).
  • Kakuda W, Lansberg MG, Thijs VN et al. Optimal definition for PWI/DWI mismatch in acute ischemic stroke patients. J. Cereb. Blood Flow Metab.28(5), 887–891 (2008).
  • Olivot JM, Mlynash M, Thijs VN et al. Relationships between infarct growth, clinical outcome, and early recanalization in diffusion and perfusion imaging for understanding stroke evolution (DEFUSE). Stroke39(8), 2257–2263 (2008).
  • Nagakane Y, Christensen S, Brekenfeld C et al. EPITHET: positive result after reanalysis using baseline diffusion-weighted imaging/perfusion-weighted imaging co-registration. Stroke42(1), 59–64 (2010).
  • Kakuda W, Hamilton S, Thijs VN et al. Optimal outcome measures for detecting clinical benefits of early reperfusion: insights from the DEFUSE Study. J. Stroke Cerebrovasc. Dis.17(4), 235–240 (2008).
  • Goldberg MP, Ransom BR. New light on white matter. Stroke34(2), 330–332 (2003).
  • Arakawa S, Wright PM, Koga M et al. Ischemic thresholds for gray and white matter: a diffusion and perfusion magnetic resonance study. Stroke37(5), 1211–1216 (2006).
  • Hoyte L, Barber PA, Buchan AM, Hill MD. The rise and fall of NMDA antagonists for ischemic stroke. Curr. Mol. Med.4(2), 131–136 (2004).
  • Koga M, Reutens DC, Wright P et al. The existence and evolution of diffusion-perfusion mismatched tissue in white and gray matter after acute stroke. Stroke36(10), 2132–2137 (2005).
  • Dewar D, Yam P, Mcculloch J. Drug development for stroke: importance of protecting cerebral white matter. Eur. J. Pharmacol.375(1–3), 41–50 (1999).
  • Micu I, Jiang Q, Coderre E et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature439(7079), 988–992 (2006).
  • Tang XN, Liu L, Yenari MA. Combination therapy with hypothermia for treatment of cerebral ischemia. J. Neurotrauma26(3), 325–331 (2009).
  • Schmid-Elsaesser R, Hungerhuber E, Zausinger S, Baethmann A, Reulen HJ. Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke30(9), 1891–1899 (1999).
  • Fagan SC, Bowes MP, Berri SA, Zivin JA. Combination treatment for acute ischemic stroke: a ray of hope? J. Stroke Cerebrovasc. Dis.8(6), 359–367 (1999).
  • Martin-Schild S, Hallevi H, Shaltoni H et al. Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia. J. Stroke Cerebrovasc. Dis.18(2), 86–96 (2009).

Website

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.