Advertisement

Acta Neuropathologica

, Volume 108, Issue 5, pp 406–412 | Cite as

A two-hour window for hypothermic modulation of early events that impact delayed opening of the rat blood-brain barrier after ischemia

  • Edward PrestonEmail author
  • Jacqueline Webster
Regular Paper

Abstract

Opening of the blood-brain barrier (BBB) and consequent edema are known to intensify 24–72 h after ischemic stroke, and research on potential ameliorative therapies in animal models may lead to improved clinical treatments to prevent brain swelling and the secondary damage it causes. In this study, post-ischemic hypothermia treatment, which is an established neuroprotective strategy, was examined for its ability to prevent delayed BBB opening in a rat model of global ischemia. Anesthetized, normothermic SD rats (340–380 g) underwent 20 min of two-vessel (carotid) occlusion plus hypotension (2VO ischemia, between 0900–1100 h). Marked cortical BBB leakiness, which developed overnight, was indicated at sacrifice 24 h post-2VO by an average six- to eightfold increase above baseline in transfer constant values (Ki ) for rate of blood to brain diffusion of intravenously delivered [3H]sucrose. A post-2VO treatment involving whole body cooling to 31.5°–32.5°C, maintenance for 6 h and rewarming to normothermia, significantly reduced BBB leakiness at 24 h, whether cooling was initiated immediately after reperfusion, or after a 1-h delay, but not after 2-h delay. Immediate hypothermia treatment reduced overall tissue injury at 24 h as evidenced by an assay of mitochondrial succinate dehydrogenase activity, and also reduced brain edema. By contrast, treatment of rats with the anti-inflammatory drugs cyclosporine A or minocycline offered no protection of BBB or mitochondria. It is concluded that hypothermic alteration of critical events during the first 2 h after prolonged ischemia powerfully mitigates the BBB damage and associated events that normally develop 24 h later.

Keywords

Ischemia Blood-brain barrier Hypothermia Stroke Vasogenic edema 

References

  1. 1.
    Busto R, Dietrich WD, Globus MY, Ginsberg MD (1989) Postischemic hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett 101:299–304CrossRefPubMedGoogle Scholar
  2. 2.
    Coimbra C, Wieloch T (1994) Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol 87:325–331CrossRefPubMedGoogle Scholar
  3. 3.
    Corbett D, Hamilton M, Colbourne F (2000) Persistent neuroprotection with prolonged postischemic hypothermia in adult rats subjected to transient middle cerebral artery occlusion. Exp Neurol 163:200–206CrossRefPubMedGoogle Scholar
  4. 4.
    Hsu CY, Lui TH, Xu J, Hogan EL, Chao J (1990) Lipid inflammatory mediators in ischemic brain edema and injury. In: Bazan NG (ed) Lipid mediators in ischemic brain damage and experimental epilepsy, new trends in lipid mediators research, vol 4. Karger, Basel, pp 85–112Google Scholar
  5. 5.
    Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM (1999) Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. Can J Neurol Sci 16:298–304Google Scholar
  6. 6.
    Huh PW, Belayev L, Zhao W, Koch S, Busto R, Ginsberg MD (2000) Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia. J Neurosurg 92:91–99PubMedGoogle Scholar
  7. 7.
    Kuroda S, Janelidze S, Siesjo BK (1999) The immunosuppressants cyclosporin A and FK506 equally ameliorate brain damage due to 30-min middle cerebral artery occlusion in hyperglycemic rats. Brain Res 835:148–153CrossRefPubMedGoogle Scholar
  8. 8.
    Mizuta K, Ohmori M, Miyashita F, Kitoh Y, Fujimura A, Mori M, Kanno T, Hashizume K, Kobayashi E (1999) Effect of pretreatment with FTY720 and cyclosporin on ischaemia-reperfusion injury of the liver in rats. J Pharm Pharmacol 51:1423–1428CrossRefPubMedGoogle Scholar
  9. 9.
    Ohno K, Pettigrew KD, Rapoport SI (1978) Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Am J Physiol 235:H299–H307PubMedGoogle Scholar
  10. 10.
    Preston E, Webster J (2000) Spectrophotometric measurement of experimental brain injury. J Neurosci Methods 94:187–192CrossRefPubMedGoogle Scholar
  11. 11.
    Preston E, Webster J (2002) Differential passage of [14C]sucrose and [3H]inulin across rat blood-brain barrier after cerebral ischemia. Acta Neuropathol 103:237–242CrossRefPubMedGoogle Scholar
  12. 12.
    Preston E, Allen M, Haas N (1983). A modified method for measurement of radiotracer permeation across the rat blood brain barrier: the problem of correcting brain uptake for intravascular tracer. J Neurosci Methods 9:45–55CrossRefPubMedGoogle Scholar
  13. 13.
    Preston E, Saunders J, Haas N, Rydzy M, Kozlowski P (1990) Selective, delayed increase in transfer constants for cerebrovascular permeation of blood-borne [3H]sucrose following forebrain ischemia in the rat. Acta Neurochir (Wien) S51:174–176Google Scholar
  14. 14.
    Preston E, Sutherland G, Finsten A (1993) Three openings of the blood-brain barrier produced by forebrain ischemia in the rat. Neurosci Lett 149:75–78CrossRefPubMedGoogle Scholar
  15. 15.
    Siesjo BK, Siesjo P (1996) Mechanisms of secondary brain injury. Eur J Anaesthesiol 13:247–268CrossRefPubMedGoogle Scholar
  16. 16.
    Smith ML, Auer RN, Siesjo BK (1984) The density and distribution of ischemic brain injury in the rat following 2–10 min forebrain ischemia. Acta Neuropathol (Berl) 64:319–332Google Scholar
  17. 17.
    Sullivan PG, Thompson M, Scheff SW (2000) Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury. Exp Neurol 161:631–637CrossRefPubMedGoogle Scholar
  18. 18.
    Sutcliffe IT, Smith HA, Stanimirovic D, Hutchison JS (2001) Effects of moderate hypothermia on IL-1 beta-induced leukocyte rolling and adhesion in pial microcirculation of mice and on proinflammatory gene expression in human cerebral endothelial cells. J Cereb Blood Flow Metab 21:1310–1319CrossRefPubMedGoogle Scholar
  19. 19.
    Thornhill J, Corbett D (2001) Therapeutic implications of hypothermic and hyperthermic temperature conditions in stroke patients. Can J Physiol Pharmacol 79:254–261CrossRefPubMedGoogle Scholar
  20. 20.
    Uchino H, Elmer E, Uchino K, Lindvall O, Siesjo BK (1995) Cyclosporin A dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat. Acta Physiol Scand 155:469–471PubMedGoogle Scholar
  21. 21.
    Wang CX, Yang T, Shuaib A (2003) Effects of minocycline alone and in combination with mild hypothermia in embolic stroke. Brain Res 963:327–329CrossRefPubMedGoogle Scholar
  22. 22.
    Xue D, Huang ZG, Smith KE, Buchan AM (1992) Immediate or delayed mild hypothermia prevent focal cerebral infarction. Brain Res 587:66–72CrossRefPubMedGoogle Scholar
  23. 23.
    Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 96:13496–13500CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Institute for Biological SciencesNational Research Council CanadaOttawaCanada

Personalised recommendations