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Metabolic Reflow as a Therapy for Ischemic Brain Injury

  • Conference paper
Early Brain Injury or Cerebral Vasospasm

Part of the book series: Acta Neurochirurgica Supplements ((NEUROCHIRURGICA,volume 110/2))

Abstract

Ischemic neuronal damage is a common feature of occlusive strokes, hemorrhagic strokes, and traumatic brain injury. In addition, ischemia can be an anticipated or unanticipated complication of a variety of surgical procedures. Most therapeutic strategies for managing ischemic injury seek to re-establish blood flow, suppress neural metabolism, and/or limit specific cellular injury cascades. An alternative therapeutic approach is to enhance the delivery of metabolic substrates to ischemic tissue. This strategy is typified by efforts to increase tissue oxygenation by elevating the levels of circulating oxygen. Our studies are examining a complementary approach in which the delivery of metabolic substrates is enhanced by facilitating the diffusion of oxygen and glucose from the vasculature into neural tissue during ischemia. This is achieved by increasing the diffusivity of small molecules in aqueous solutions, such as plasma and interstitial fluid. The carotenoid compound, trans-sodium crocetinate (TSC) is capable of increasing oxygen and glucose diffusivity, and our studies demonstrate that TSC increases cerebral tissue oxygenation in the penumbra of a focal ischemic event. In addition, TSC treatment reduces the volume of cerebral infarction in rodent models of both permanent and temporary focal ischemia. This strategy of “metabolic reflow” thus blunts the metabolic challenge in partially-perfused tissue and reduces ischemic neural injury.

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References

  1. Al-Waili NS, Butler GJ, Beale J, Abdullah MS, Hamilton RW, Lee BY, et al. Hyperbaric oxygen in the treatment of patients with cerebral stroke, brain trauma, and neurologic disease. Adv Ther. 2005;22:659–678.

    Article  PubMed  CAS  Google Scholar 

  2. Anderson DC, Bottini AG, Jagiella WM, Westphal B, Ford S, Rockswold GL, et al. A pilot study of hyperbaric oxygen in the treatment of human stroke. Stroke 1991;22:1137–1142.

    Article  PubMed  CAS  Google Scholar 

  3. Bennett MH, Wasiak J, Schnabel A, Kranke P, French C. Hyperbaric oxygen therapy for acute ischaemic stroke. Cochrane Database Syst Rev. 2005;20:CD004954

    Google Scholar 

  4. Beynon C, Sun L, Marti HH, Heiland S, Veltkamp R. Delayed hyperbaric oxygenation is more effective than early prolonged normobaric hyperoxia in experimental focal cerebral ischemia. Neurosci Lett. 2007;425:141–145.

    Article  PubMed  CAS  Google Scholar 

  5. Burt JT, Kapp JP, Smith RR. Hyperbaric oxygen and cerebral infarction in the gerbil. Surg Neurol.1987;28:265–268.

    Article  PubMed  CAS  Google Scholar 

  6. Carson S, McDonagh M, Russman B, Helfand M. Hyperbaric oxygen therapy for stroke: a systematic review of the evidence. Clin Rehabil. 2005;19:819–833.

    Article  PubMed  Google Scholar 

  7. Cheng YD, Al-Khoury L, Zivin JA. Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx 2004;1:36–45.

    Article  PubMed  Google Scholar 

  8. Delgado-Mederos R, Rovira A, Alvarez-Sabin J, Ribo M, Munuera J, Rubiera M, et al. Speed of tPA-induced clot lysis predicts DWI lesion evolution in acute stroke. Stroke 2007;38:955–960

    Article  PubMed  CAS  Google Scholar 

  9. Dirnagl U. Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab. 2006;26:1465–1478.

    Article  PubMed  Google Scholar 

  10. Donnan GA. The 2007 Feinberg lecture: a new road map for neuroprotection. Stroke 2008;39:242

    Article  PubMed  Google Scholar 

  11. Eschenfelder CC, Krug R, Yusofi AF, Meyne JK, Herdegen T, Koch A, et al. Neuroprotection by oxygen in acute transient focal cerebral ischemia is dose dependent and shows superiority of hyperbaric oxygenation. Cerebrovasc Dis. 2008;25:193–201.

    Article  PubMed  CAS  Google Scholar 

  12. Fisher M. Recommendations for advancing development of acute stroke therapies: stroke Therapy Academic Industry Roundtable 3. Stroke 2003;34:1539–1546.

    Article  PubMed  CAS  Google Scholar 

  13. Flynn EP, Auer RN. Eubaric hyperoxemia and experimental cerebral infarction. Ann Neurol. 2002;52:566–572.

    Article  PubMed  Google Scholar 

  14. Gainer JL, Rudolph DB, Caraway DL. The effect of crocetin on hemorrhagic shock in rats. Circ Shock. 1993;41:1–7.

    PubMed  CAS  Google Scholar 

  15. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008;55:363–389.

    Article  PubMed  CAS  Google Scholar 

  16. Ginsberg MD. Current status of neuroprotection for cerebral ischemia: synoptic overview. Stroke 2009;40:S111–S114.

    Article  PubMed  Google Scholar 

  17. Helms AK, Whelan HT, Torbey MT. Hyperbaric oxygen therapy of acute ischemic stroke. Stroke. 2007;38:1137; author reply 1138–1139.

    Article  PubMed  Google Scholar 

  18. Henninger N, Bouley J, Nelligan JM, Sicard KM, Fisher M. Normobaric hyperoxia delays perfusion/diffusion mismatch evolution, reduces infarct volume, and differentially affects neuronal cell death pathways after suture middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 2007;27:1632–1642.

    Article  PubMed  Google Scholar 

  19. Henninger N, Kuppers-Tiedt L, Sicard KM, Gunther A, Schneider D, Schwab S. Neuroprotective effect of hyperbaric oxygen therapy monitored by MR-imaging after embolic stroke in rats. Exp Neurol. 2006;201:316–323.

    Article  PubMed  CAS  Google Scholar 

  20. Hiramatsu K, Kassell NF, Goto Y, Soleau S, Lee KS. A reproducible model of reversible, focal, neocortical ischemia in Sprague-Dawley rat. Acta Neurochir (Wien). 1993;120:66–71.

    Article  CAS  Google Scholar 

  21. Holloway GM, Gainer JL. The carotenoid crocetin enhances pulmonary oxygenation. J Appl Physiol. 1998;65:683–686.

    Google Scholar 

  22. Huxley VH, Kutchai H. The effect of the red cell membrane and a diffusion boundary layer on the rate of oxygen uptake by human erythrocytes. J Physiol. 1981;316:75–83.

    PubMed  CAS  Google Scholar 

  23. Huxley VH, Kutchai H. Effect of diffusion boundary layers on the initial uptake of O2 by red cells. Theory versus experiment. Microvasc Res. 1983;26:89–107.

    Article  PubMed  CAS  Google Scholar 

  24. Kawamura S, Yasui N, Shirasawa M, Fukasawa H. Therapeutic effects of hyperbaric oxygenation on acute focal cerebral ischemia in rats. Surg Neurol. 1990;34:101–106.

    Article  PubMed  CAS  Google Scholar 

  25. Kim HY, Singhal AB, Lo EH. Normobaric hyperoxia extends the reperfusion window in focal cerebral ischemia. Ann Neurol. 2005;57:571–575.

    Article  PubMed  Google Scholar 

  26. Labiche LA, Grotta JC. Clinical trials for cytoprotection in stroke. NeuroRx 2004;1:46–70.

    Article  PubMed  Google Scholar 

  27. Laidig K, Dagget V, Gainer J. Altering diffusivity in biological solutions via change of solution structure and dynamics. J Am Chem Soc. 1998;120:9394–9395.

    Article  CAS  Google Scholar 

  28. Liu W, Sood R, Chen Q, Sakoglu U, Hendren J, Cetin O, et al. Normobaric hyperoxia inhibits NADPH oxidase-mediated matrix metalloproteinase-9 induction in cerebral microvessels in experimental stroke. J Neurochem. 2008;107:1196–1205.

    Article  PubMed  CAS  Google Scholar 

  29. Macleod MR, van der Worp HB, Sena ES, Howells DW, Dirnagl U, Donnan GA. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke 2008;39:2824–2829.

    Article  PubMed  Google Scholar 

  30. Manabe H, Okonkwo DO, Gainer JL, Clarke R, Lee KS. Protection against focal ischemic injury to the brain by trans-sodium crocetinate. Journal of Neurosurgery 2010;113(4). Epub:12/09 with podcast.

    Google Scholar 

  31. Moustafa RR, Baron J. Perfusion thresholds in cerebral ischemia. In: Donnan GA, Baron J, Davis SM, Sharp FR, editors. The ischemic penumbra. New York: Informa Healthcare USA, Inc.; 2002

    Google Scholar 

  32. Neubauer RA, End E. Hyperbaric oxygenation as an adjunct therapy in strokes due to thrombosis. A review of 122 patients. Stroke 1980;11:297–300.

    Article  PubMed  CAS  Google Scholar 

  33. Nighoghossian N, Trouillas P. Hyperbaric oxygen in the treatment of acute ischemic stroke: an unsettled issue. J Neurol Sci. 1997;150:27–31.

    Article  PubMed  CAS  Google Scholar 

  34. Nighoghossian N, Trouillas P, Adeleine P, Salord F. Hyperbaric oxygen in the treatment of acute ischemic stroke. A double-blind pilot study. Stroke 1995;26:1369–1372.

    Article  PubMed  CAS  Google Scholar 

  35. O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–477.

    Article  PubMed  Google Scholar 

  36. Okonkwo DO, Wagner J, Melon DE, Alden T, Stone JR, Helm GA, et al. Trans-sodium crocetinate increases oxygen delivery to brain parenchyma in rats on oxygen supplementation. Neurosci Lett. 2003;352:97–100.

    Article  PubMed  CAS  Google Scholar 

  37. Ostrowski RP, Colohan AR, Zhang JH. Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2005;25:554–571.

    Article  PubMed  CAS  Google Scholar 

  38. 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. Stroke 2009;40:577–581.

    Article  PubMed  CAS  Google Scholar 

  39. Qin Z, Karabiyikoglu M, Hua Y, Silbergleit R, He Y, Keep RF, et al. Hyperbaric oxygen-induced attenuation of hemorrhagic transformation after experimental focal transient cerebral ischemia. Stroke 2007;38:1362–1367.

    Article  PubMed  CAS  Google Scholar 

  40. Ribo M, Alvarez-Sabin J, Montaner J, Romero F, Delgado P, Rubiera M, et al. Temporal profile of recanalization after intravenous tissue plasminogen activator: selecting patients for rescue reperfusion techniques. Stroke 2006;37:1000–1004.

    Article  PubMed  CAS  Google Scholar 

  41. Rogalewski A, Schneider A, Ringelstein EB, Schabitz WR. Toward a multimodal neuroprotective treatment of stroke. Stroke 2006;37:1129–1136.

    Article  PubMed  Google Scholar 

  42. Roy JW, Graham MC, Griffin AM, Gainer JL. A novel fluid resuscitation therapy for hemorrhagic shock. Shock 1998;10:213–217.

    Article  PubMed  CAS  Google Scholar 

  43. Rusyniak DE, Kirk MA, May JD, Kao LW, Brizendine EJ, Welch JL, et al. Hyperbaric oxygen therapy in acute ischemic stroke: results of the hyperbaric oxygen in Acute Ischemic Stroke Trial Pilot Study. Stroke 2003;34:571–574.

    Article  PubMed  Google Scholar 

  44. 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. 2007;205:20–25.

    Article  PubMed  CAS  Google Scholar 

  45. Schabitz WR, Schade H, Heiland S, Kollmar R, Bardutzky J, Henninger N, et al. Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI. Stroke 2004;35:1175–1179.

    Article  PubMed  Google Scholar 

  46. Seyde WC, McKernan DJ, Laudeman T, Gainer JL, Longnecker DE. Carotenoid compound crocetin improves cerebral oxygenation in hemorrhaged rats. J Cereb Blood Flow Metab. 1986;6:703–707.

    Article  PubMed  CAS  Google Scholar 

  47. Shin HK, Dunn AK, Jones PB, Boas DA, Lo EH, Moskowitz MA, et al. Normobaric hyperoxia improves cerebral blood flow and oxygenation, and inhibits peri-infarct depolarizations in experimental focal ischaemia. Brain 2007;130:1631–1642.

    Article  PubMed  Google Scholar 

  48. Singhal AB. A review of oxygen therapy in ischemic stroke. Neurol Res. 2007;29:173–183.

    Article  PubMed  Google Scholar 

  49. Singhal AB, Benner T, Roccatagliata L, Koroshetz WJ, Schaefer PW, Lo EH, et al. A pilot study of normobaric oxygen therapy in acute ischemic stroke. Stroke 2005;36:797–802.

    Article  PubMed  Google Scholar 

  50. Singhal AB, Dijkhuizen RM, Rosen BR, Lo EH. Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke. Neurology 2002;58:945–952.

    Article  PubMed  Google Scholar 

  51. Singhal AB, Wang X, Sumii T, Mori T, Lo EH. Effects of normobaric hyperoxia in a rat model of focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab. 22:861–868.

    Google Scholar 

  52. Stennett AK, Dempsey GL, Gainer JL. trans-Sodium crocetinate and diffusion enhancement. J Phys Chem B. 2006;110:18078–18080.

    Article  PubMed  CAS  Google Scholar 

  53. Stroke Therapy Academic Industry Roundtable. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999;30:2752–2758.

    Article  Google Scholar 

  54. Stroke Therapy Academic Industry Roundtable. Recommendations for clinical trial evaluation of acute stroke therapies. Stroke 2001;32:1598–1606.

    Article  Google Scholar 

  55. Sunami K, Takeda Y, Hashimoto M, Hirakawa M. Hyperbaric oxygen reduces infarct volume in rats by increasing oxygen supply to the ischemic periphery. Crit Care Med. 2000;28:2831–2836.

    Article  PubMed  CAS  Google Scholar 

  56. Veltkamp R, Siebing DA, Sun L, Heiland S, Bieber K, Marti HH, et al. Hyperbaric oxygen reduces blood-brain barrier damage and edema after transient focal cerebral ischemia. Stroke 2005;36:1679–1683.

    Article  PubMed  Google Scholar 

  57. Veltkamp R, Warner DS, Domoki F, Brinkhous AD, Toole JF, Busija DW. Hyperbaric oxygen decreases infarct size and behavioral deficit after transient focal cerebral ischemia in rats. Brain Res. 2000;853:68–73.

    Article  PubMed  CAS  Google Scholar 

  58. Wang Y, Yoshimura R, Manabe H, Lee KS. Effect of trans-sodium crocetinate in a model of intracranial hemorrhage. Society for Neuroscience Abstracts #472. Washington, DC (2008).

    Google Scholar 

  59. Weinstein PR, Anderson GG, Telles DA. Results of hyperbaric oxygen therapy during temporary middle cerebral artery occlusion in unanesthetized cats. Neurosurgery 1987;20:518–524.

    Article  PubMed  CAS  Google Scholar 

  60. Yakovlev AG, Faden AI. Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRx 2004;1:5–16.

    Article  PubMed  Google Scholar 

  61. Yenari M, Kitagawa K, Lyden P, Perez-Pinzon M. Metabolic downregulation: a key to successful neuroprotection? Stroke 2008;39:2910–2917.

    Article  PubMed  CAS  Google Scholar 

  62. Zhang JH, Lo T, Mychaskiw G, Colohan A. Mechanisms of hyperbaric oxygen and neuroprotection in stroke. Pathophysiology 2005;12:63–77.

    Article  PubMed  CAS  Google Scholar 

  63. Zhang JH, Singhal AB, Toole JF. Oxygen therapy in ischemic stroke. Stroke 2002;34:e152–3; author reply e153–e155.

    Article  Google Scholar 

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Acknowledgement

Supported by NS057168 and GM08328.

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Authors and Affiliations

  1. Department of Neuroscience, University of Virginia, Charlottesville, VA, USA

    Hiroaki Manabe, Yi Wang, Ryo Yoshimura, Yu Cai, Mark Fitzgerald, Ryon Clarke & Kevin S. Lee

  2. Department of Neurological Surgery, University of Virginia, Charlottesville, VA, USA

    Hiroaki Manabe, Yi Wang, Ryo Yoshimura, Yu Cai, Mark Fitzgerald, Ryon Clarke & Kevin S. Lee

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  1. Hiroaki Manabe
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  2. Yi Wang
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  3. Ryo Yoshimura
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  4. Yu Cai
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  7. Kevin S. Lee
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Correspondence to Kevin S. Lee .

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Editors and Affiliations

  1. Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Gaotanyan 30, Chongqing, 400038, China

    Hua Feng

  2. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China

    Ying Mao

  3. Departments of Physiology and Neurosurgery, Loma Linda University School of Medicine, Risley Hall, Room 223, 92354, Loma Linda, California, USA

    John H. Zhang

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Manabe, H. et al. (2011). Metabolic Reflow as a Therapy for Ischemic Brain Injury. In: Feng, H., Mao, Y., Zhang, J.H. (eds) Early Brain Injury or Cerebral Vasospasm. Acta Neurochirurgica Supplements, vol 110/2. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0356-2_16

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  • DOI: https://doi.org/10.1007/978-3-7091-0356-2_16

  • Publisher Name: Springer, Vienna

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  • Online ISBN: 978-3-7091-0356-2

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