Impairment and Pharmacological Protection of the Blood Brain Barrier After Head Trauma

  • Esther Shohami
  • Reuven Reich


The unique microenvironment within the central nervous system depends upon the integrity of the blood brain barrier (BBB), which under normal conditions prevents the passage of macromolecules and ions into the brain. The BBB plays an integral role in the inflammatory response by producing a variety of cytokines, adhesion molecules, metalloproteinases, serine proteases, products of the arachidonic acid metabolic cascade and nitric oxide (Webb and Muir, 2000). Increased BBB permeability may occur by either direct mechanical opening of tight junctions between endothelial cells (Wahl et al, 1988), or by biochemical mechanisms (Wei et al., 1986; Trembovler et al., 1999; for review see Kochanek et al., 2000). When BBB permeability is increased, vasogenic edema is developed, contributing to brain swelling and intracranial pressure, thus exacerbating the secondary injury. Traumatic brain injury, ischemia, and inflammatory diseases induce the local formation and release of harmful mediators such as neurotransmitters, reactive oxygen species and cytokines. These, in turn, induce the evolution of secondary damage within the brain, eliciting disruption of the BBB, edema and neuronal cell death that are accompanied by motor and cognitive deficits. Local inflammation is one of the early responses of the brain to injury (Rothwell and Hopkins, 1995; Merril and Benveniste, 1996, Shohami et al., 1999).


Traumatic Brain Injury Blood Brain Barrier Focal Cerebral Ischemia Vasogenic Edema Evans Blue 
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  1. Beit-Yannai, E., Zhang, R., Trembovler, V., Samuni, A., and Shohami E. 1996, Cerebroprotective effect of stable nitroxide radicals in closed head injury in the rat. Brain Res. 717: 22–28.PubMedCrossRefGoogle Scholar
  2. Brigham, K.L., and Meyrick, B., 1986, Endotoxin and lung injury. Am. Rev. Repir. Dis. 133: 913–927.Google Scholar
  3. Chen, Y., Shohami, E., Constantini, S. and Weinstock, M., 1998, Rivastigmine, a brain selective acetylcholinesterase inhibitor, ameliorates cognitive and motor deficits induced by closed head injury in the mouse. J. Neurotrauma. 15: 231–237.PubMedCrossRefGoogle Scholar
  4. Chopp, M., Zhang, R.L., Chen, H., Li, Y,. Jiang, N., and Rusche, J.R. 1994, Postischemic administration of an anti-Mac-1 antibody reduces ischemia cell damage after transient middle cerebral artery occlusion in rats. Stroke 25: 869–875.PubMedCrossRefGoogle Scholar
  5. Claudio, L., Martiney, J.A., and Brosnan, CF. 1994, Ultrastructural studies of the blood-retina barrier after exposure to interleukin-1 beta or tumor necrosis factor-alpha. Lab Incest. 70: 850–861.Google Scholar
  6. Fujimura, M., Gasche. Y., Morite-Fujimura, Y., Massengale, J., Kawase, M., and Chan, P.H. 1999, Early appearance of matrix metallo[proteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res. 842: 92–100.PubMedCrossRefGoogle Scholar
  7. Gasche, Y., Fujimura, M., Morita-Fujimura, Y., Copin, J.C., Kawase, M., Messengale, J., and Chan, P.H., 1999, Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J Cereb Blood Flow Metab 19: 1020–1028.PubMedCrossRefGoogle Scholar
  8. Horwitz, L.D., Kaufman, D., Kong, Y.N., 1997, In antibody to leukocyte integrins attenuates coronary vascular injury due to ischemia and reperfusion in dogs. Am. J. Physiol.-Heart Circ Physiol. 41: H618–H624.Google Scholar
  9. Kochanek, P.M., Clark, R.S.B., Rupper, R.A., et al. 2000, Biochemical, cellular and molecular mechanisms in the evolution of damage after severe traumatic brain injury in infants and children: Lessons learned from the bedside. Pediatr Crit Care Med 1: 4–19.PubMedCrossRefGoogle Scholar
  10. Lukes, A., Mun-Bryce, S., Lukes, M., and Rosenberg, G.A., 1999, Extracellular matrix degradation by metalloproteinases and central nervous system diseases. Mol Neurobiol 19: 267–284.PubMedCrossRefGoogle Scholar
  11. Merril, J.E., and Benveniste, E.N. 1996, Cytokines in inflammatory brain lesions: helpful and harmful. Trends in Neuroscience 19, 331–338.CrossRefGoogle Scholar
  12. Mun-Bryce, S., and Rosenberg, G.A., 1998 Gelatinase B modulates selective opening of the blood-brain barrier during inflammation. Am J Physiol. 274: R1203–1211.PubMedGoogle Scholar
  13. Rosenberg, G.A., Estrada, E.Y., and Dencoff, J.E., 1998, Matrix metallooproteinases and TIMPx are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke, 29: 2189–2195.PubMedCrossRefGoogle Scholar
  14. Rothwell, N.J., and Hopkins, S.J., 1995, Cytokines and the nervous system II: action and mechanisms of action. Trends in Neuroscience 18, 130–136.CrossRefGoogle Scholar
  15. Shapira, Y., Setton, D., Artru, A., and Shohami, E., 1993, Blood brain barrier, cerebral edema and neurological function following closed head injury in the rats. Anesth. Analg, 77: 141–148.PubMedGoogle Scholar
  16. Shohami, E., Bass, R., Wallach, D., Yamin, A., and Gallily, R, 1996, Inhibition of Tumor Necrosis Factor a activity in rat brain is associated with cerebroprotection after closed head injury. J. Cereb. Blood Flow Metabol. 16: 378–384.Google Scholar
  17. Shohami, E., Ginis, I. and Hallenbeck, J.M., 1999, Dual Role of Tumor Necrosis Factor Alpha in Brain Injury. Cytokines and Growth Factors Reviews. 10: 119–130.CrossRefGoogle Scholar
  18. Shohami, E., Novikov, M., and Mechoulam, R., 1993, A non psychotropic cannabinoid, HU-211 has cerebroprotective effects after closed head injury. J Neuro trauma, 10: 109–119.Google Scholar
  19. Shohami, E., and Mechoulam, R., 2000, Dexanabinol (HU-211): a Nonpsychotropic Cannabinoid with Neuroprotective Properties. Drug Develop. Res. 50: 211–215.CrossRefGoogle Scholar
  20. Soares, H.D., Hicks, R.R., Smith, D., and McIntosh, T.K., 1995, Inflammatory Leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosci 15: 8223–8233.PubMedGoogle Scholar
  21. Trembovler, V., Beit-Yannai, E., Younis, F., Gallily, R., Horowitz, M., and Shohami, E., 1999. Antioxidants Attenuate Acute Toxicity of Tumor Necrosis Factor a Induced by Brain Injury in Rat. J Interferon Cytokine Res. 19: 791–795.PubMedCrossRefGoogle Scholar
  22. Wahl, M., Unterberg, A., Baethmann, A., and Schilling, L., 1988, Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema. J. Cerebr. Blood Flow Metabol 8: 621–634.CrossRefGoogle Scholar
  23. Webb, A.A., and Muir, G.D., 2000, The blood brain barrier and its role in inflammation. J Vet Intern Med 14: 399–411.PubMedCrossRefGoogle Scholar
  24. Wei, E.P., Ellison, M.D., Kontos, H.A., and Povlishock, J.T., 1986, 02 radicals in arachidonate-induced increased blood-brain barrier permeability to proteins. Am J physiol 251: H693–H699.PubMedGoogle Scholar
  25. Whalen, M.J., Carlos, T.M., Kochanek, P.M., Clark, R.S.B., Heineman, S., et al. 1999, Neutrophils do not mediate blood brain barrier permeability early after controlled cortical impact in rats. J Neurotrauma, 16: 583–594.PubMedCrossRefGoogle Scholar
  26. Zhang, R., Shohami, E., Beit-Yannai, E., Bass, R., Trembovler, V., and Samuni, A. 1998, Mechanism of brain protection by nitroxide radicals in experimental model of closed head injury. Free Rad. Biol. Med. 24: 332–340.PubMedCrossRefGoogle Scholar
  27. Zhang, R.L., Chopp, M., Zhang, Z.G, et al. 1996, E-selectin in focal cerebral ischemia and reperfusion in the rat. J. Cereb Blood Flow Metabol 16: 1126–1136.Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Esther Shohami
    • 1
  • Reuven Reich
    • 1
  1. 1.Department of PharmacologyThe Hebrew University School of PharmacyJerusalemIsrael

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