EFFECT OF THE COMBINATION OF NEUROPROTECTIVE THERAPIES ON INFARCT SIZE AND NEUROLOGICAL OUTCOME AFTER STROKE
Beroertes met beroerde uitkomst: is er hoop?
08.54u. Er komt een oproep binnen voor de MUG. Een meisje heeft haar oma van 73 jaar aangetroffen op de grond in de gang. Wanneer de MUG ter plaatse zijn, treffen de spoedarts en verpleger een verwarde, angstige dame aan. Haar rechter lichaamshelft is verlamd en veel meer dan ja of nee kan ze niet uitspreken. In het ziekenhuis wordt een scan uitgevoerd die die vermoedelijke diagnose bevestigt: een beroerte. Of de dame zal overleven en in welke toestand ze zal zijn, valt nog af te wachten, maar één ding is zeker: de lijdensweg is begonnen.
Wereldwijd zijn beroertes de op één na voornaamste doodsoorzaak bij volwassenen. Wie overleeft, kampt vaak met ernstige beperkingen op korte en lange termijn, zoals verlamming, spraak- en geheugenstoornissen. In Europa zijn beroertes jaarlijks voor bijna 1,1 miljoen doden per jaar verantwoordelijk. 15% van de vrouwen en 10% van de mannen sterft ten gevolge van deze aandoening. Kortom: iedereen kent wel een slachtoffer. De uitdaging bestaat er nu in een gepast therapeutisch antwoord te vinden. Is er hoop op een doorbraak?
Hersenen in ademnood
Om een behandeling te optimaliseren of nieuwe opties te ontdekken, moeten we eerst en vooral goed begrijpen waar we mee te maken hebben. Een beroerte ontstaat meestal wanneer een bloedklonter een bloedvat afsluit en zo de bloedstroom naar de hersenen onderbreekt. In de minderheid van de gevallen gaat het om een bloeding. Onze hersenen zijn ontzettend gevoelig aan de gevolgen van zo’n onderbreking van de bloedtoevoer. Binnen de kortste keren is alle zuurstof opgebruikt en komen onze hersenen in de problemen. Een centrale groep cellen rond de afsluiting gaat onherroepelijk verloren, maar het lot van de “penumbra”, een zone rond deze kern, hangt af van wat er in de volgende uren gebeurt. Hoe langer de afsluiting, hoe erger de schade: “time is brain”. De ischemische cascade, de complexe opeenvolging van schadelijke gebeurtenissen na zuurstoftekort, is reeds grondig bestudeerd en het is duidelijk dat veel therapeutische stoffen een invloed kunnen hebben op de uitkomst na een beroerte.
rt-PA en neuroprotectie
Ondanks uitgebreid onderzoek, blijven artsen in hun therapeutisch arsenaal voorlopig ernstig beperkt. Misschien had je het zelf al bedacht: de bloedtoevoer herstellen is de belangrijkste stap in de behandeling. Dit gebeurt met rt-PA, een stof die de klonter oplost. Een groot probleem is echter dat rt-PA binnen de 4,5 uur na het begin van de beroerte moet toegediend worden om enig effect te hebben en dikwijls is niet bekend hoe lang de klonter het bloedvat afsluit. Neuroprotectie, een tweede, fundamenteel verschillende strategie houdt dan ook in de hersenen weerbaarder te maken tegen zuurstoftekort, onafhankelijk van een herstel van de bloedtoevoer. Op dit moment lijkt therapeutische hypothermie de meest beloftevolle optie binnen deze strategie. Afkoeling van het lichaam, en van de hersenen in het bijzonder, heeft een effect op een hele waaier aan stapjes in de ischemische cascade en kan dus op verschillende niveaus de uitkomst beïnvloeden. Meerdere studies hebben het gunstige effect van hypothermie al vastgelegd, waarbij er zelfs bewezen is dat het tijdsvenster voor andere behandelingen kan verlengd worden. Deze laatste eigenschap is van ontzettend groot belang, omdat er sowieso een delay zit tussen het begin van de afsluiting, de diagnose en de behandeling. Een andere neuroprotectieve behandeling is de toediening van IGF-1, insulineachtige groeifactor-1. Deze stof grijpt ook aan op verschillende stappen in de ischemische cascade en heeft zijn nut in verscheidene dierproeven bewezen. Maar weer is de tijd een stoorfactor: enkel wanneer IGF-1 binnen het halfuur wordt toegediend, is er enige verbetering van de uitkomst te verwachten. Die 30 minuutjes zijn om voor je het weet.
Of rats and men
Een logische invalshoek voor onze studie was dan ook IGF-1 en hypothermie combineren om zo te controleren of ze samen de uitkomst na een beroerte nog beter zouden kunnen beïnvloeden dan apart en of het tijdsvenster voor IGF-1 toediening verlengd zou kunnen worden. In de naam van de wetenschap hebben we ratten een beroerte doen krijgen en ze nadien op verschillende manieren behandeld. Zo bekwamen we groepen met andere behandelingsschema’s, simpel gesteld: wel of geen hypothermie, wel of geen IGF-1 en IGF-1 op verschillende tijdstippen. We evalueerden de uitkomst op twee manieren: functioneel en histologisch. Met behulp van een serie kleine testjes keken we na hoe goed de zenuwfuncties van de ratten bewaard waren gebleven. Histologisch gingen we na hoe groot de aangetaste zone in de hersenen was door de hersenen op een speciale manier te snijden, te kleuren en met de microscoop te bekijken. Uit dit onderzoek bleek dat de ratten die behandeld werden het wel degelijk beter deden dan de ratten die niet behandeld werden en er was ook een betere uitkomst bij de combinatiebehandeling ten opzichte van de aparte behandelingen, maar jammer genoeg konden we dit niet statistisch verzilveren. Onder andere het feit dat we een onvoldoende aantal ratten hadden in elke groep vormde een belangrijke hinderpaal in het onderzoek.
Is er hoop?
Ondanks het gebrek aan een statistisch belangrijke verbetering van de uitkomst, blijven we positief. Mits uitbreiding van de groepen kunnen we in de toekomst misschien wel aantonen dat de combinatie van hypothermie en IGF-1 een goede strategie is om de gevolgen van een beroerte in te dijken. Een miraculeus wondermiddel dat al het leed na een beroerte wegneemt, zal waarschijnlijk niet snel gevonden worden. Maar als we stapje voor stapje de behandeling verfijnen, zullen vast en zeker heel wat mensen geholpen kunnen worden.
Bibliografie
ADDIN EN.REFLIST 1. Minino AM, Xu J, Kochanek KD. Deaths: preliminary data for 2008. National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System. 2010;59(2):1-52.
2. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367(9524):1747-57.
3. Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: evidence, costs, and effects on individuals and populations. Lancet. 1999;354(9188):1457-63.
4. Durukan A, Tatlisumak T. Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacology, biochemistry, and behavior. 2007;87(1):179-97.
5. Smith WS. Pathophysiology of focal cerebral ischemia: a therapeutic perspective. Journal of vascular and interventional radiology : JVIR. 2004;15(1 Pt 2):S3-12.
6. Polderman KH. Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence. Intensive care medicine. 2004;30(4):556-75.
7. Ceulemans AG, Zgavc T, Kooijman R, Hachimi-Idrissi S, Sarre S, Michotte Y. The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. Journal of neuroinflammation. 2010;7:74.
8. Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke; a journal of cerebral circulation. 2009;40(5):e331-9.
9. Hou ST, MacManus JP. Molecular mechanisms of cerebral ischemia-induced neuronal death. International review of cytology. 2002;221:93-148.
10. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology. 2008;55(3):363-89.
11. Lipton P. Ischemic cell death in brain neurons. Physiological reviews. 1999;79(4):1431-568.
12. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends in neurosciences. 1999;22(9):391-7.
13. Wu TC, Grotta JC. Hypothermia for acute ischaemic stroke. Lancet neurology. 2013;12(3):275-84.
14. Siesjo BK, Bengtsson F, Grampp W, Theander S. Calcium, excitotoxins, and neuronal death in the brain. Annals of the New York Academy of Sciences. 1989;568:234-51.
15. Weinberger JM. Evolving therapeutic approaches to treating acute ischemic stroke. Journal of the neurological sciences. 2006;249(2):101-9.
16. Barone FC, Feuerstein GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1999;19(8):819-34.
17. Gonzalez-Ibarra FP, Varon J, Lopez-Meza EG. Therapeutic hypothermia: critical review of the molecular mechanisms of action. Frontiers in neurology. 2011;2:4.
18. Ientile R, Caccamo D, Macaione V, Torre V, Macaione S. NMDA-evoked excitotoxicity increases tissue transglutaminase in cerebellar granule cells. Neuroscience. 2002;115(3):723-9.
19. Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nature medicine. 1997;3(10):1089-95.
20. Zhao H, Steinberg GK, Sapolsky RM. General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2007;27(12):1879-94.
21. Yenari MA, Han HS. Influence of hypothermia on post-ischemic inflammation: role of nuclear factor kappa B (NFkappaB). Neurochemistry international. 2006;49(2):164-9.
22. Liu P, Xu B, Hock CE, Nagele R, Sun FF, Wong PY. NO modulates P-selectin and ICAM-1 mRNA expression and hemodynamic alterations in hepatic I/R. The American journal of physiology. 1998;275(6 Pt 2):H2191-8.
23. Lai AY, Todd KG. Microglia in cerebral ischemia: molecular actions and interactions. Canadian journal of physiology and pharmacology. 2006;84(1):49-59.
24. Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002;39(3):279-91.
25. Lucivero V, Prontera M, Mezzapesa DM, Petruzzellis M, Sancilio M, Tinelli A, et al. Different roles of matrix metalloproteinases-2 and -9 after human ischaemic stroke. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2007;28(4):165-70.
26. Gasche Y, Fujimura M, Morita-Fujimura Y, Copin JC, Kawase M, Massengale J, et al. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1999;19(9):1020-8.
27. Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2000;20(12):1681-9.
28. Jiang X, Namura S, Nagata I. Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neuroscience letters. 2001;305(1):41-4.
29. del Zoppo GJ, Milner R, Mabuchi T, Hung S, Wang X, Berg GI, et al. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke; a journal of cerebral circulation. 2007;38(2 Suppl):646-51.
30. Chu LS, Wei EQ, Yu GL, Fang SH, Zhou Y, Wang ML, et al. Pranlukast reduces neutrophil but not macrophage/microglial accumulation in brain after focal cerebral ischemia in mice. Acta pharmacologica Sinica. 2006;27(3):282-8.
31. Fukuda S, Warner DS. Cerebral protection. British journal of anaesthesia. 2007;99(1):10-7.
32. Kollmar R, Schwab S. Hypothermia in focal ischemia: implications of experiments and experience. Journal of neurotrauma. 2009;26(3):377-86.
33. Krieger DW, Yenari MA. Therapeutic hypothermia for acute ischemic stroke: what do laboratory studies teach us? Stroke; a journal of cerebral circulation. 2004;35(6):1482-9.
34. Liu L, Yenari MA. Therapeutic hypothermia: neuroprotective mechanisms. Frontiers in bioscience : a journal and virtual library. 2007;12:816-25.
35. Olsen TS, Weber UJ, Kammersgaard LP. Therapeutic hypothermia for acute stroke. Lancet neurology. 2003;2(7):410-6.
36. Lanier WL. Cerebral metabolic rate and hypothermia: their relationship with ischemic neurologic injury. Journal of neurosurgical anesthesiology. 1995;7(3):216-21.
37. Soukup J, Zauner A, Doppenberg EM, Menzel M, Gilman C, Bullock R, et al. Relationship between brain temperature, brain chemistry and oxygen delivery after severe human head injury: the effect of mild hypothermia. Neurological research. 2002;24(2):161-8.
38. Kimura T, Sako K, Tanaka K, Kusakabe M, Tanaka T, Nakada T. Effect of mild hypothermia on energy state recovery following transient forebrain ischemia in the gerbil. Experimental brain research. 2002;145(1):83-90.
39. Milde LN. Clinical use of mild hypothermia for brain protection: a dream revisited. Journal of neurosurgical anesthesiology. 1992;4(3):211-5.
40. Linares G, Mayer SA. Hypothermia for the treatment of ischemic and hemorrhagic stroke. Critical care medicine. 2009;37(7 Suppl):S243-9.
41. Phillips KF, Deshpande LS, DeLorenzo RJ. Hypothermia reduces calcium entry via the N-methyl-D-aspartate and ryanodine receptors in cultured hippocampal neurons. European journal of pharmacology. 2013;698(1-3):186-92.
42. Friedman LK, Ginsberg MD, Belayev L, Busto R, Alonso OF, Lin B, et al. Intraischemic but not postischemic hypothermia prevents non-selective hippocampal downregulation of AMPA and NMDA receptor gene expression after global ischemia. Brain research Molecular brain research. 2001;86(1-2):34-47.
43. Li J, Benashski S, McCullough LD. Post-stroke hypothermia provides neuroprotection through inhibition of AMP-activated protein kinase. Journal of neurotrauma. 2011;28(7):1281-8.
44. Zhao H, Wang JQ, Shimohata T, Sun G, Yenari MA, Sapolsky RM, et al. Conditions of protection by hypothermia and effects on apoptotic pathways in a rat model of permanent middle cerebral artery occlusion. Journal of neurosurgery. 2007;107(3):636-41.
45. Maier CM, Ahern K, Cheng ML, Lee JE, Yenari MA, Steinberg GK. Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke; a journal of cerebral circulation. 1998;29(10):2171-80.
46. Van Hemelrijck A, Hachimi-Idrissi S, Sarre S, Ebinger G, Michotte Y. Post-ischaemic mild hypothermia inhibits apoptosis in the penumbral region by reducing neuronal nitric oxide synthase activity and thereby preventing endothelin-1-induced hydroxyl radical formation. The European journal of neuroscience. 2005;22(6):1327-37.
47. Wang GJ, Deng HY, Maier CM, Sun GH, Yenari MA. Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience. 2002;114(4):1081-90.
48. Truettner JS, Suzuki T, Dietrich WD. The effect of therapeutic hypothermia on the expression of inflammatory response genes following moderate traumatic brain injury in the rat. Brain research Molecular brain research. 2005;138(2):124-34.
49. Zhang H, Zhou M, Zhang J, Mei Y, Sun S, Tong E. Therapeutic effect of post-ischemic hypothermia duration on cerebral ischemic injury. Neurological research. 2008;30(4):332-6.
50. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. The New England journal of medicine. 1997;336(15):1066-71.
51. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nature reviews Immunology. 2002;2(10):725-34.
52. Han HS, Karabiyikoglu M, Kelly S, Sobel RA, Yenari MA. Mild hypothermia inhibits nuclear factor-kappaB translocation in experimental stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2003;23(5):589-98.
53. Webster CM, Kelly S, Koike MA, Chock VY, Giffard RG, Yenari MA. Inflammation and NFkappaB activation is decreased by hypothermia following global cerebral ischemia. Neurobiology of disease. 2009;33(2):301-12.
54. Hill WD, Hess DC, Carroll JE, Wakade CG, Howard EF, Chen Q, et al. The NF-kappaB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia. Brain research bulletin. 2001;55(3):375-86.
55. Flamm ES, Demopoulos HB, Seligman ML, Poser RG, Ransohoff J. Free radicals in cerebral ischemia. Stroke; a journal of cerebral circulation. 1978;9(5):445-7.
56. Kitagawa K, Matsumoto M, Oda T, Niinobe M, Hata R, Handa N, et al. Free radical generation during brief period of cerebral ischemia may trigger delayed neuronal death. Neuroscience. 1990;35(3):551-8.
57. Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. Journal of neurochemistry. 1995;65(4):1704-11.
58. Globus MY, Busto R, Lin B, Schnippering H, Ginsberg MD. Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation. Journal of neurochemistry. 1995;65(3):1250-6.
59. Maier CM, Sun GH, Cheng D, Yenari MA, Chan PH, Steinberg GK. Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia. Neurobiology of disease. 2002;11(1):28-42.
60. Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM. Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques. 1999;26(4):298-304.
61. Chi OZ, Liu X, Weiss HR. Effects of mild hypothermia on blood-brain barrier disruption during isoflurane or pentobarbital anesthesia. Anesthesiology. 2001;95(4):933-8.
62. Jurkovich GJ, Pitt RM, Curreri PW, Granger DN. Hypothermia prevents increased capillary permeability following ischemia-reperfusion injury. The Journal of surgical research. 1988;44(5):514-21.
63. MacLellan CL, Clark DL, Silasi G, Colbourne F. Use of prolonged hypothermia to treat ischemic and hemorrhagic stroke. Journal of neurotrauma. 2009;26(3):313-23.
64. Baker CJ, Onesti ST, Barth KN, Prestigiacomo CJ, Solomon RA. Hypothermic protection following middle cerebral artery occlusion in the rat. Surgical neurology. 1991;36(3):175-80.
65. Kader A, Brisman MH, Maraire N, Huh JT, Solomon RA. The effect of mild hypothermia on permanent focal ischemia in the rat. Neurosurgery. 1992;31(6):1056-60; discussion 60-1.
66. Morikawa E, Ginsberg MD, Dietrich WD, Duncan RC, Kraydieh S, Globus MY, et al. The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1992;12(3):380-9.
67. Ridenour TR, Warner DS, Todd MM, McAllister AC. Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats. Stroke; a journal of cerebral circulation. 1992;23(5):733-8.
68. Doerfler A, Schwab S, Hoffmann TT, Engelhorn T, Forsting M. Combination of decompressive craniectomy and mild hypothermia ameliorates infarction volume after permanent focal ischemia in rats. Stroke; a journal of cerebral circulation. 2001;32(11):2675-81.
69. Dezena RA, Colli BO, Carlotti Junior CG, Tirapelli LF. Pre, intra and post-ischemic hypothermic neuroprotection in temporary focal cerebral ischemia in rats: morphometric analysis. Arquivos de neuro-psiquiatria. 2012;70(8):609-16.
70. Maier CM, Sun GH, Kunis D, Yenari MA, Steinberg GK. Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. Journal of neurosurgery. 2001;94(1):90-6.
71. Hashimoto M, Zhao L, Nowak TS, Jr. Temporal thresholds for infarction and hypothermic protection in Long-Evans rats: factors affecting apparent 'reperfusion injury' after transient focal ischemia. Stroke; a journal of cerebral circulation. 2008;39(2):421-6.
72. Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1995;15(11):7250-60.
73. Colbourne F, Corbett D, Zhao Z, Yang J, Buchan AM. Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2000;20(12):1702-8.
74. Clark DL, Penner M, Orellana-Jordan IM, Colbourne F. Comparison of 12, 24 and 48 h of systemic hypothermia on outcome after permanent focal ischemia in rat. Experimental neurology. 2008;212(2):386-92.
75. van der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR. Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain : a journal of neurology. 2007;130(Pt 12):3063-74.
76. Hemmen TM, Lyden PD. Hypothermia after acute ischemic stroke. Journal of neurotrauma. 2009;26(3):387-91.
77. Clark DL, Penner M, Wowk S, Orellana-Jordan I, Colbourne F. Treatments (12 and 48 h) with systemic and brain-selective hypothermia techniques after permanent focal cerebral ischemia in rat. Experimental neurology. 2009;220(2):391-9.
78. Florian B, Vintilescu R, Balseanu AT, Buga AM, Grisk O, Walker LC, et al. Long-term hypothermia reduces infarct volume in aged rats after focal ischemia. Neuroscience letters. 2008;438(2):180-5.
79. Yanamoto H, Nagata I, Nakahara I, Tohnai N, Zhang Z, Kikuchi H. Combination of intraischemic and postischemic hypothermia provides potent and persistent neuroprotection against temporary focal ischemia in rats. Stroke; a journal of cerebral circulation. 1999;30(12):2720-6; discussion 6.
80. Yanamoto H, Nagata I, Niitsu Y, Zhang Z, Xue JH, Sakai N, et al. Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia. Stroke; a journal of cerebral circulation. 2001;32(1):232-9.
81. Kollmar R, Blank T, Han JL, Georgiadis D, Schwab S. Different degrees of hypothermia after experimental stroke: short- and long-term outcome. Stroke; a journal of cerebral circulation. 2007;38(5):1585-9.
82. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke; a journal of cerebral circulation. 2001;32(9):2033-5.
83. Berger C, Xia F, Kohrmann M, Schwab S. Hypothermia in acute stroke--slow versus fast rewarming an experimental study in rats. Experimental neurology. 2007;204(1):131-7.
84. Steiner T, Friede T, Aschoff A, Schellinger PD, Schwab S, Hacke W. Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery. Stroke; a journal of cerebral circulation. 2001;32(12):2833-5.
85. Lampe JW, Becker LB. State of the art in therapeutic hypothermia. Annual review of medicine. 2011;62:79-93.
86. Sessler DI. Defeating normal thermoregulatory defenses: induction of therapeutic hypothermia. Stroke; a journal of cerebral circulation. 2009;40(11):e614-21.
87. De Georgia MA, Krieger DW, Abou-Chebl A, Devlin TG, Jauss M, Davis SM, et al. Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology. 2004;63(2):312-7.
88. Bernard SA, Buist M. Induced hypothermia in critical care medicine: a review. Critical care medicine. 2003;31(7):2041-51.
89. Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Annals of emergency medicine. 1997;30(2):146-53.
90. Ao H, Moon JK, Tashiro M, Terasaki H. Delayed platelet dysfunction in prolonged induced canine hypothermia. Resuscitation. 2001;51(1):83-90.
91. Valeri CR, Feingold H, Cassidy G, Ragno G, Khuri S, Altschule MD. Hypothermia-induced reversible platelet dysfunction. Annals of surgery. 1987;205(2):175-81.
92. Wolberg AS, Meng ZH, Monroe DM, 3rd, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. The Journal of trauma. 2004;56(6):1221-8.
93. Den Hertog HM, van der Worp HB, Tseng MC, Dippel DW. Cooling therapy for acute stroke. The Cochrane database of systematic reviews. 2009(1):CD001247.
94. Merchant RM, Abella BS, Peberdy MA, Soar J, Ong ME, Schmidt GA, et al. Therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets. Critical care medicine. 2006;34(12 Suppl):S490-4.
95. Sagalyn E, Band RA, Gaieski DF, Abella BS. Therapeutic hypothermia after cardiac arrest in clinical practice: review and compilation of recent experiences. Critical care medicine. 2009;37(7 Suppl):S223-6.
96. Zweifler RM, Sessler DI. Thermoregulatory vasococonstriction and shivering impede therapeutic hypothermia in acute ischemic stroke patients. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 1996;6(2):100-3.
97. Mokhtarani M, Mahgoub AN, Morioka N, Doufas AG, Dae M, Shaughnessy TE, et al. Buspirone and meperidine synergistically reduce the shivering threshold. Anesthesia and analgesia. 2001;93(5):1233-9.
98. Cheng C, Matsukawa T, Sessler DI, Ozaki M, Kurz A, Merrifield B, et al. Increasing mean skin temperature linearly reduces the core-temperature thresholds for vasoconstriction and shivering in humans. Anesthesiology. 1995;82(5):1160-8.
99. Guluma KZ, Hemmen TM, Olsen SE, Rapp KS, Lyden PD. A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2006;13(8):820-7.
100. Kammersgaard LP, Rasmussen BH, Jorgensen HS, Reith J, Weber U, Olsen TS. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: A case-control study: the Copenhagen Stroke Study. Stroke; a journal of cerebral circulation. 2000;31(9):2251-6.
101. Stroke Therapy Academic Industry R. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke; a journal of cerebral circulation. 1999;30(12):2752-8.
102. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. The New England journal of medicine. 1995;333(24):1581-7.
103. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768-74.
104. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England journal of medicine. 2008;359(13):1317-29.
105. Wahlgren N, Ahmed N, Davalos A, Hacke W, Millan M, Muir K, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008;372(9646):1303-9.
106. Horn J, de Haan RJ, Vermeulen M, Limburg M. Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke; a journal of cerebral circulation. 2001;32(2):461-5.
107. Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M. Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke; a journal of cerebral circulation. 2001;32(10):2433-8.
108. Horn J, Limburg M. Calcium antagonists for acute ischemic stroke. The Cochrane database of systematic reviews. 2000(2):CD001928.
109. Cai Z, Lin S, Rhodes PG. Neuroprotective effects of N-acetylaspartylglutamate in a neonatal rat model of hypoxia-ischemia. European journal of pharmacology. 2002;437(3):139-45.
110. Pin JP, Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995;34(1):1-26.
111. Minematsu K, Fisher M, Li L, Sotak CH. Diffusion and perfusion magnetic resonance imaging studies to evaluate a noncompetitive N-methyl-D-aspartate antagonist and reperfusion in experimental stroke in rats. Stroke; a journal of cerebral circulation. 1993;24(12):2074-81.
112. Schabitz WR, Li F, Fisher M. The N-methyl-D-aspartate antagonist CNS 1102 protects cerebral gray and white matter from ischemic injury following temporary focal ischemia in rats. Stroke; a journal of cerebral circulation. 2000;31(7):1709-14.
113. Gladstone DJ, Black SE, Hakim AM, Heart, Stroke Foundation of Ontario Centre of Excellence in Stroke R. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke; a journal of cerebral circulation. 2002;33(8):2123-36.
114. Albers GW, Atkinson RP, Kelley RE, Rosenbaum DM. Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group. Stroke; a journal of cerebral circulation. 1995;26(2):254-8.
115. Albers GW, Goldstein LB, Hall D, Lesko LM, Aptiganel Acute Stroke I. Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA : the journal of the American Medical Association. 2001;286(21):2673-82.
116. Muir KW, Grosset DG, Lees KR. Clinical pharmacology of CNS 1102 in volunteers. Annals of the New York Academy of Sciences. 1995;765:279-89; discussion 98.
117. Muir KW, Lees KR, Ford I, Davis S, Intravenous Magnesium Efficacy in Stroke Study I. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet. 2004;363(9407):439-45.
118. Olney JW. Neurotoxicity of NMDA receptor antagonists: an overview. Psychopharmacology bulletin. 1994;30(4):533-40.
119. Davis SM, Albers GW, Diener HC, Lees KR, Norris J. Termination of Acute Stroke Studies Involving Selfotel Treatment. ASSIST Steering Committed. Lancet. 1997;349(9044):32.
120. Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, et al. Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist. Stroke; a journal of cerebral circulation. 2000;31(2):347-54.
121. Dawson DA, Wadsworth G, Palmer AM. A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke. Brain research. 2001;892(2):344-50.
122. Bordi F, Pietra C, Ziviani L, Reggiani A. The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAo model of focal ischemia in the rat. Experimental neurology. 1997;145(2 Pt 1):425-33.
123. Bordi F, Terron A, Reggiani A. The neuroprotective glycine receptor antagonist GV150526 does not produce neuronal vacuolization or cognitive deficits in rats. European journal of pharmacology. 1999;378(2):153-60.
124. Reggiani A, Pietra C, Arban R, Marzola P, Guerrini U, Ziviani L, et al. The neuroprotective activity of the glycine receptor antagonist GV150526: an in vivo study by magnetic resonance imaging. European journal of pharmacology. 2001;419(2-3):147-53.
125. van der Worp HB, de Haan P, Morrema E, Kalkman CJ. Methodological quality of animal studies on neuroprotection in focal cerebral ischaemia. Journal of neurology. 2005;252(9):1108-14.
126. Gorelick PB. Neuroprotection in acute ischaemic stroke: a tale of for whom the bell tolls? Lancet. 2000;355(9219):1925-6.
127. Gill R. The pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists and their role in cerebral ischaemia. Cerebrovascular and brain metabolism reviews. 1994;6(3):225-56.
128. Xue D, Huang ZG, Barnes K, Lesiuk HJ, Smith KE, Buchan AM. Delayed treatment with AMPA, but not NMDA, antagonists reduces neocortical infarction. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1994;14(2):251-61.
129. Takahashi M, Kohara A, Shishikura J, Kawasaki-Yatsugi S, Ni JW, Yatsugi S, et al. YM872: a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist. CNS drug reviews. 2002;8(4):337-52.
130. Elting JW, Sulter GA, Kaste M, Lees KR, Diener HC, Hommel M, et al. AMPA antagonist ZK200775 in patients with acute ischemic stroke: possible glial cell toxicity detected by monitoring of S-100B serum levels. Stroke; a journal of cerebral circulation. 2002;33(12):2813-8.
131. Li H, Buchan AM. Treatment with an AMPA antagonist 12 hours following severe normothermic forebrain ischemia prevents CA1 neuronal injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1993;13(6):933-9.
132. Lees KR, Asplund K, Carolei A, Davis SM, Diener HC, Kaste M, et al. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Lancet. 2000;355(9219):1949-54.
133. Wilby MJ, Hutchinson PJ. The pharmacology of chlormethiazole: a potential neuroprotective agent? CNS drug reviews. 2004;10(4):281-94.
134. Chaulk D, Wells J, Evans S, Jackson D, Corbett D. Long-term effects of clomethiazole in a model of global ischemia. Experimental neurology. 2003;182(2):476-82.
135. Sydserff SG, Cross AJ, West KJ, Green AR. The effect of chlormethiazole on neuronal damage in a model of transient focal ischaemia. British journal of pharmacology. 1995;114(8):1631-5.
136. Sydserff SG, Cross AJ, Green AR. The neuroprotective effect of chlormethiazole on ischaemic neuronal damage following permanent middle cerebral artery ischaemia in the rat. Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration. 1995;4(3):323-8.
137. Ovbiagele B, Kidwell CS, Starkman S, Saver JL. Neuroprotective agents for the treatment of acute ischemic stroke. Current neurology and neuroscience reports. 2003;3(1):9-20.
138. Sahota P, Savitz SI. Investigational therapies for ischemic stroke: neuroprotection and neurorecovery. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2011;8(3):434-51.
139. Saver JL, Starkman S, Eckstein M, Stratton S, Pratt F, Hamilton S, et al. Methodology of the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) phase 3 trial: Part 1 - rationale and general methods. International journal of stroke : official journal of the International Stroke Society. 2014;9(2):215-9.
140. Saver JL, Starkman S, Eckstein M, Stratton S, Pratt F, Hamilton S, et al. Methodology of the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) phase 3 trial: Part 2 - prehospital study methods. International journal of stroke : official journal of the International Stroke Society. 2014;9(2):220-5.
141. Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK. Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1999;19(7):778-87.
142. Sydserff SG, Borelli AR, Green AR, Cross AJ. Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window. British journal of pharmacology. 2002;135(1):103-12.
143. Sena E, Wheble P, Sandercock P, Macleod M. Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke; a journal of cerebral circulation. 2007;38(2):388-94.
144. Namura S, Nagata I, Takami S, Masayasu H, Kikuchi H. Ebselen reduces cytochrome c release from mitochondria and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Stroke; a journal of cerebral circulation. 2001;32(8):1906-11.
145. Takasago T, Peters EE, Graham DI, Masayasu H, Macrae IM. Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion. British journal of pharmacology. 1997;122(6):1251-6.
146. Imai H, Masayasu H, Dewar D, Graham DI, Macrae IM. Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia. Stroke; a journal of cerebral circulation. 2001;32(9):2149-54.
147. Salom JB, Perez-Asensio FJ, Burguete MC, Marin N, Pitarch C, Torregrosa G, et al. Single-dose ebselen does not afford sustained neuroprotection to rats subjected to severe focal cerebral ischemia. European journal of pharmacology. 2004;495(1):55-62.
148. Watanabe T, Yuki S, Egawa M, Nishi H. Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions. The Journal of pharmacology and experimental therapeutics. 1994;268(3):1597-604.
149. Amemiya S, Kamiya T, Nito C, Inaba T, Kato K, Ueda M, et al. Anti-apoptotic and neuroprotective effects of edaravone following transient focal ischemia in rats. European journal of pharmacology. 2005;516(2):125-30.
150. Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y, Urabe T. Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke; a journal of cerebral circulation. 2005;36(10):2220-5.
151. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, et al. NXY-059 for acute ischemic stroke. The New England journal of medicine. 2006;354(6):588-600.
152. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al. NXY-059 for the treatment of acute ischemic stroke. The New England journal of medicine. 2007;357(6):562-71.
153. van der Worp HB, Kappelle LJ, Algra A, Bar PR, Orgogozo JM, Ringelstein EB, et al. The effect of tirilazad mesylate on infarct volume of patients with acute ischemic stroke. Neurology. 2002;58(1):133-5.
154. Adibhatla RM, Hatcher JF. Citicoline mechanisms and clinical efficacy in cerebral ischemia. Journal of neuroscience research. 2002;70(2):133-9.
155. Trovarelli G, de Medio GE, Dorman RV, Piccinin GL, Horrocks LA, Porcellati G. Effect of cytidine diphosphate choline (CDP-choline) on ischemia-induced alterations of brain lipid in the gerbil. Neurochemical research. 1981;6(8):821-33.
156. Weiss GB. Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci. 1995;56(9):637-60.
157. Krupinski J, Ferrer I, Barrachina M, Secades JJ, Mercadal J, Lozano R. CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase activation following middle cerebral artery occlusion in the rat. Neuropharmacology. 2002;42(6):846-54.
158. Hurtado O, Moro MA, Cardenas A, Sanchez V, Fernandez-Tome P, Leza JC, et al. Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport. Neurobiology of disease. 2005;18(2):336-45.
159. Mir C, Clotet J, Aledo R, Durany N, Argemi J, Lozano R, et al. CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons. Journal of molecular neuroscience : MN. 2003;20(1):53-60.
160. Rao AM, Hatcher JF, Dempsey RJ. Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain research. 2001;893(1-2):268-72.
161. Aronowski J, Strong R, Grotta JC. Citicoline for treatment of experimental focal ischemia: histologic and behavioral outcome. Neurological research. 1996;18(6):570-4.
162. Davalos A, Alvarez-Sabin J, Castillo J, Diez-Tejedor E, Ferro J, Martinez-Vila E, et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet. 2012;380(9839):349-57.
163. Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA, et al. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke; a journal of cerebral circulation. 2003;34(11):2543-8.
164. Enlimomab Acute Stroke Trial I. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology. 2001;57(8):1428-34.
165. Sughrue ME, Connolly ES, Jr. Effectively bridging the preclinical/clinical gap: the results of the ASTIN trial. Stroke; a journal of cerebral circulation. 2004;35(4):e81-2; author reply e-2.
166. Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM, et al. Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke; a journal of cerebral circulation. 1995;26(8):1438-42; discussion 43.
167. Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, et al. Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke; a journal of cerebral circulation. 2003;34(3):745-51.
168. Kollmar R, Henninger N, Urbanek C, Schwab S. G-CSF, rt-PA and combination therapy after experimental thromboembolic stroke. Experimental & translational stroke medicine. 2010;2:9.
169. Gibson CL, Bath PM, Murphy SP. G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2005;25(4):431-9.
170. Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, et al. Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation. 2004;110(13):1847-54.
171. Lee ST, Chu K, Jung KH, Ko SY, Kim EH, Sinn DI, et al. Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain research. 2005;1058(1-2):120-8.
172. Sehara Y, Hayashi T, Deguchi K, Zhang H, Tsuchiya A, Yamashita T, et al. Potentiation of neurogenesis and angiogenesis by G-CSF after focal cerebral ischemia in rats. Brain research. 2007;1151:142-9.
173. Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. The Journal of clinical investigation. 2005;115(8):2083-98.
174. Schabitz WR, Laage R, Vogt G, Koch W, Kollmar R, Schwab S, et al. AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke; a journal of cerebral circulation. 2010;41(11):2545-51.
175. Shyu WC, Lin SZ, Lee CC, Liu DD, Li H. Granulocyte colony-stimulating factor for acute ischemic stroke: a randomized controlled trial. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2006;174(7):927-33.
176. Sprigg N, Bath PM, Zhao L, Willmot MR, Gray LJ, Walker MF, et al. Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke; a journal of cerebral circulation. 2006;37(12):2979-83.
177. Kennedy EP. The synthesis of cytidine diphosphate choline, cytidine diphosphate ethanolamine, and related compounds. The Journal of biological chemistry. 1956;222(1):185-91.
178. Ringelstein EB, Thijs V, Norrving B, Chamorro A, Aichner F, Grond M, et al. Granulocyte colony-stimulating factor in patients with acute ischemic stroke: results of the AX200 for Ischemic Stroke trial. Stroke; a journal of cerebral circulation. 2013;44(10):2681-7.
179. Dawson TM, Steiner JP, Dawson VL, Dinerman JL, Uhl GR, Snyder SH. Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(21):9808-12.
180. Nito C, Kamiya T, Ueda M, Arii T, Katayama Y. Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats. Brain research. 2004;1008(2):179-85.
181. Wayner DD, Burton GW, Ingold KU, Locke S. Quantitative measurement of the total, peroxyl radical-trapping antioxidant capability of human blood plasma by controlled peroxidation. The important contribution made by plasma proteins. FEBS letters. 1985;187(1):33-7.
182. Halliwell B. Albumin--an important extracellular antioxidant? Biochemical pharmacology. 1988;37(4):569-71.
183. He P, Curry FE. Albumin modulation of capillary permeability: role of endothelial cell [Ca2+]i. The American journal of physiology. 1993;265(1 Pt 2):H74-82.
184. Curry S, Mandelkow H, Brick P, Franks N. Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nature structural biology. 1998;5(9):827-35.
185. Belayev L, Busto R, Zhao W, Clemens JA, Ginsberg MD. Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats. Journal of neurosurgery. 1997;87(4):595-601.
186. Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke; a journal of cerebral circulation. 2001;32(2):553-60.
187. Belayev L, Pinard E, Nallet H, Seylaz J, Liu Y, Riyamongkol P, et al. Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke; a journal of cerebral circulation. 2002;33(4):1077-84.
188. Belayev L, Zhao W, Pattany PM, Weaver RG, Huh PW, Lin B, et al. Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia. Stroke; a journal of cerebral circulation. 1998;29(12):2587-99.
189. Huh PW, Belayev L, Zhao W, Busto R, Saul I, Ginsberg MD. The effect of high-dose albumin therapy on local cerebral perfusion after transient focal cerebral ischemia in rats. Brain research. 1998;804(1):105-13.
190. Nimmagadda A, Park HP, Prado R, Ginsberg MD. Albumin therapy improves local vascular dynamics in a rat model of primary microvascular thrombosis: a two-photon laser-scanning microscopy study. Stroke; a journal of cerebral circulation. 2008;39(1):198-204.
191. Rodriguez de Turco EB, Belayev L, Liu Y, Busto R, Parkins N, Bazan NG, et al. Systemic fatty acid responses to transient focal cerebral ischemia: influence of neuroprotectant therapy with human albumin. Journal of neurochemistry. 2002;83(3):515-24.
192. Reinhart WH, Nagy C. Albumin affects erythrocyte aggregation and sedimentation. European journal of clinical investigation. 1995;25(7):523-8.
193. Ginsberg MD, Palesch YY, Hill MD, Martin RH, Moy CS, Barsan WG, et al. High-dose albumin treatment for acute ischaemic stroke (ALIAS) Part 2: a randomised, double-blind, phase 3, placebo-controlled trial. Lancet neurology. 2013;12(11):1049-58.
194. Goossens J, Hachimi-Idrissi S. Combination of therapeutic hypothermia and other neuroprotective strategies after an ischemic cerebral insult. Current neuropharmacology. 2014;12(5):399-412.
195. Bi M, Ma Q, Zhang S, Li J, Zhang Y, Lin L, et al. Local mild hypothermia with thrombolysis for acute ischemic stroke within a 6-h window. Clinical neurology and neurosurgery. 2011;113(9):768-73.
196. Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke; a journal of cerebral circulation. 2010;41(10):2265-70.
197. Frazzini VI, Winfree CJ, Choudhri HF, Prestigiacomo CJ, Solomon RA. Mild hypothermia and MK-801 have similar but not additive degrees of cerebroprotection in the rat permanent focal ischemia model. Neurosurgery. 1994;34(6):1040-5; discussion 5-6.
198. Van Hemelrijck A, Hachimi-Idrissi S, Sarre S, Ebinger G, Michotte Y. Neuroprotective effect of N-acetyl-aspartyl-glutamate in combination with mild hypothermia in the endothelin-1 rat model of focal cerebral ischaemia. Journal of neurochemistry. 2005;95(5):1287-97.
199. Campbell K, Meloni BP, Knuckey NW. Combined magnesium and mild hypothermia (35 degrees C) treatment reduces infarct volumes after permanent middle cerebral artery occlusion in the rat at 2 and 4, but not 6 h. Brain research. 2008;1230:258-64.
200. Campbell K, Knuckey NW, Brookes LM, Meloni BP. Efficacy of mild hypothermia (35 degrees C) and moderate hypothermia (33 degrees C) with and without magnesium when administered 30min post-reperfusion after 90min of middle cerebral artery occlusion in Spontaneously Hypertensive rats. Brain research. 2013;1502:47-54.
201. Scholler K, Zausinger S, Baethmann A, Schmid-Elsaesser R. Neuroprotection in ischemic stroke--combination drug therapy and mild hypothermia in a rat model of permanent focal cerebral ischemia. Brain research. 2004;1023(2):272-8.
202. 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. Stroke; a journal of cerebral circulation. 1999;30(9):1891-9.
203. Zausinger S, Scholler K, Plesnila N, Schmid-Elsaesser R. Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in rats. Stroke; a journal of cerebral circulation. 2003;34(9):2246-51.
204. Nito C, Kamiya T, Amemiya S, Katoh K, Katayama Y. The neuroprotective effect of a free radical scavenger and mild hypothermia following transient focal ischemia in rats. Acta neurochirurgica Supplement. 2003;86:199-203.
205. Sahin S, Alkan T, Temel SG, Tureyen K, Tolunay S, Korfali E. Effects of citicoline used alone and in combination with mild hypothermia on apoptosis induced by focal cerebral ischemia in rats. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2010;17(2):227-31.
206. Chen J, Fredrickson V, Ding Y, Cheng H, Wang N, Ling F, et al. Enhanced neuroprotection by local intra-arterial infusion of human albumin solution and local hypothermia. Stroke; a journal of cerebral circulation. 2013;44(1):260-2.
207. Guan J, Bennet L, Gluckman PD, Gunn AJ. Insulin-like growth factor-1 and post-ischemic brain injury. Progress in neurobiology. 2003;70(6):443-62.
208. Russo VC, Gluckman PD, Feldman EL, Werther GA. The insulin-like growth factor system and its pleiotropic functions in brain. Endocrine reviews. 2005;26(7):916-43.
209. McMorris FA, McKinnon RD. Regulation of oligodendrocyte development and CNS myelination by growth factors: prospects for therapy of demyelinating disease. Brain pathology. 1996;6(3):313-29.
210. Zumkeller W. The effect of insulin-like growth factors on brain myelination and their potential therapeutic application in myelination disorders. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 1997;1(4):91-101.
211. Pahlman S, Meyerson G, Lindgren E, Schalling M, Johansson I. Insulin-like growth factor I shifts from promoting cell division to potentiating maturation during neuronal differentiation. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(22):9994-8.
212. Knusel B, Hefti F. Trophic actions of IGF-I, IGF-II and insulin on cholinergic and dopaminergic brain neurons. Advances in experimental medicine and biology. 1991;293:351-60.
213. Caroni P, Grandes P. Nerve sprouting in innervated adult skeletal muscle induced by exposure to elevated levels of insulin-like growth factors. The Journal of cell biology. 1990;110(4):1307-17.
214. Aizenman Y, de Vellis J. Brain neurons develop in a serum and glial free environment: effects of transferrin, insulin, insulin-like growth factor-I and thyroid hormone on neuronal survival, growth and differentiation. Brain research. 1987;406(1-2):32-42.
215. Kooijman R, Sarre S, Michotte Y, De Keyser J. Insulin-like growth factor I: a potential neuroprotective compound for the treatment of acute ischemic stroke? Stroke; a journal of cerebral circulation. 2009;40(4):e83-8.
216. Sanderson TH, Kumar R, Murariu-Dobrin AC, Page AB, Krause GS, Sullivan JM. Insulin activates the PI3K-Akt survival pathway in vulnerable neurons following global brain ischemia. Neurological research. 2009;31(9):947-58.
217. Cheng HL, Steinway M, Delaney CL, Franke TF, Feldman EL. IGF-I promotes Schwann cell motility and survival via activation of Akt. Molecular and cellular endocrinology. 2000;170(1-2):211-5.
218. Parrizas M, Saltiel AR, LeRoith D. Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. The Journal of biological chemistry. 1997;272(1):154-61.
219. Baker NL, Carlo Russo V, Bernard O, D'Ercole AJ, Werther GA. Interactions between bcl-2 and the IGF system control apoptosis in the developing mouse brain. Brain research Developmental brain research. 1999;118(1-2):109-18.
220. Bake S, Selvamani A, Cherry J, Sohrabji F. Blood brain barrier and neuroinflammation are critical targets of IGF-1-mediated neuroprotection in stroke for middle-aged female rats. PloS one. 2014;9(3):e91427.
221. De Geyter D, Stoop W, Sarre S, De Keyser J, Kooijman R. Neuroprotective efficacy of subcutaneous insulin-like growth factor-I administration in normotensive and hypertensive rats with an ischemic stroke. Neuroscience. 2013;250:253-62.
222. Schabitz WR, Hoffmann TT, Heiland S, Kollmar R, Bardutzky J, Sommer C, et al. Delayed neuroprotective effect of insulin-like growth factor-i after experimental transient focal cerebral ischemia monitored with mri. Stroke; a journal of cerebral circulation. 2001;32(5):1226-33.
223. Pete G, Hu Y, Walsh M, Sowers J, Dunbar JC. Insulin-like growth factor-I decreases mean blood pressure and selectively increases regional blood flow in normal rats. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine. 1996;213(2):187-92.
224. Walsh MF, Barazi M, Pete G, Muniyappa R, Dunbar JC, Sowers JR. Insulin-like growth factor I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide. Endocrinology. 1996;137(5):1798-803.
225. Cao N, Lau S, Nguyen TT, White PJ. Characterization of the acute cardiovascular effects of intravenously administered insulin-like growth factor-I in conscious Sprague-Dawley rats. Clinical and experimental pharmacology & physiology. 2006;33(12):1190-5.
226. Liu XF, Fawcett JR, Hanson LR, Frey WH, 2nd. The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2004;13(1):16-23.
227. Liu XF, Fawcett JR, Thorne RG, DeFor TA, Frey WH, 2nd. Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage. Journal of the neurological sciences. 2001;187(1-2):91-7.
228. Liu XF, Fawcett JR, Thorne RG, Frey WH, 2nd. Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neuroscience letters. 2001;308(2):91-4.
229. Rizk NN, Myatt-Jones J, Rafols J, Dunbar JC. Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine. 2007;31(1):66-71.
230. Wang JM, Hayashi T, Zhang WR, Li F, Iwai M, Abe K. Reduction of ischemic damage by application of insulin-like growth factor-1 in rat brain after transient ischemia. Acta medica Okayama. 2001;55(1):25-30.
231. Wang JM, Hayashi T, Zhang WR, Sakai K, Shiro Y, Abe K. Reduction of ischemic brain injury by topical application of insulin-like growth factor-I after transient middle cerebral artery occlusion in rats. Brain research. 2000;859(2):381-5.
232. Lin S, Rhodes PG, Cai Z. Whole body hypothermia broadens the therapeutic window of intranasally administered IGF-1 in a neonatal rat model of cerebral hypoxia-ischemia. Brain research. 2011;1385:246-56.
233. Gilmour RS, Prosser CG, Fleet IR, Cocco L, Saunders JC, Brown KD, et al. From animal to molecule: aspects of the biology of insulin-like growth factors. The British journal of cancer Supplement. 1988;9:23-30.
234. Hill JM, Lesniak MA, Pert CB, Roth J. Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience. 1986;17(4):1127-38.
235. Lesniak MA, Hill JM, Kiess W, Rojeski M, Pert CB, Roth J. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin. Endocrinology. 1988;123(4):2089-99.
236. Guan J, Williams CE, Skinner SJ, Mallard EC, Gluckman PD. The effects of insulin-like growth factor (IGF)-1, IGF-2, and des-IGF-1 on neuronal loss after hypoxic-ischemic brain injury in adult rats: evidence for a role for IGF binding proteins. Endocrinology. 1996;137(3):893-8.
237. Carlsson-Skwirut C, Lake M, Hartmanis M, Hall K, Sara VR. A comparison of the biological activity of the recombinant intact and truncated insulin-like growth factor 1 (IGF-1). Biochimica et biophysica acta. 1989;1011(2-3):192-7.
238. Russo VC, Werther GA. Des (1-3) IGF-I potently enhances differentiated cell growth in olfactory bulb organ culture. Growth factors. 1994;11(4):301-11.
239. Rosenthal SM, Brunetti A, Brown EJ, Mamula PW, Goldfine ID. Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II. The Journal of clinical investigation. 1991;87(4):1212-9.
240. Lagina AT, 3rd, Calo L, Deogracias M, Sanderson T, Kumar R, Wider J, et al. Combination therapy with insulin-like growth factor-1 and hypothermia synergistically improves outcome after transient global brain ischemia in the rat. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2013;20(4):344-51.
241. 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; a journal of cerebral circulation. 1995;26(4):627-34; discussion 35.
242. Weston RM, Jones NM, Jarrott B, Callaway JK. Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2007;27(1):100-14.
243. Tatlisumak T, Takano K, Carano RA, Fisher M. Effect of basic fibroblast growth factor on experimental focal ischemia studied by diffusion-weighted and perfusion imaging. Stroke; a journal of cerebral circulation. 1996;27(12):2292-7; discussion 8.
244. Guan J, Gunn AJ, Sirimanne ES, Tuffin J, Gunning MI, Clark R, et al. The window of opportunity for neuronal rescue with insulin-like growth factor-1 after hypoxia-ischemia in rats is critically modulated by cerebral temperature during recovery. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2000;20(3):513-9.
245. Miyazawa T, Tamura A, Fukui S, Hossmann KA. Effect of mild hypothermia on focal cerebral ischemia. Review of experimental studies. Neurological research. 2003;25(5):457-64.
246. Noor R, Wang CX, Shuaib A. Hyperthermia masks the neuroprotective effects of tissue plaminogen activator. Stroke; a journal of cerebral circulation. 2005;36(3):665-9.
247. Ranke MB. Insulin-like growth factor-I treatment of growth disorders, diabetes mellitus and insulin resistance. Trends in endocrinology and metabolism: TEM. 2005;16(4):190-7.
248. Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, Group GHISC. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. The Journal of clinical endocrinology and metabolism. 2007;92(3):902-10.
249. Jabri N, Schalch DS, Schwartz SL, Fischer JS, Kipnes MS, Radnik BJ, et al. Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients. Diabetes. 1994;43(3):369-74.
250. Clemmons DR, Moses AC, Sommer A, Jacobson W, Rogol AD, Sleevi MR, et al. Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2005;15(4):265-74.
251. Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. The New England journal of medicine. 1993;329(9):665-6.
