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Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury

Abstract

Traumatic brain injury (TBI) is the leading cause of death in young adults and children. The treatment of TBI in the acute phase has improved substantially; however, the prevention and management of long-term complications remain a challenge. Blood–brain barrier (BBB) breakdown has often been documented in patients with TBI, but the role of such vascular pathology in neurological dysfunction has only recently been explored. Animal studies have demonstrated that BBB breakdown is involved in the initiation of transcriptional changes in the neurovascular network that ultimately lead to delayed neuronal dysfunction and degeneration. Brain imaging data have confirmed the high incidence of BBB breakdown in patients with TBI and suggest that such pathology could be used as a biomarker in the clinic and in drug trials. Here, we review the neurological consequences of TBI, focusing on the long-term complications of such injuries. We present the clinical evidence for involvement of BBB breakdown in TBI and examine the primary and secondary mechanisms that underlie such pathology. We go on to consider the consequences of BBB injury, before analyzing potential mechanisms linking vascular pathology to neuronal dysfunction and degeneration, and exploring possible targets for treatment. Finally, we highlight areas for future basic research and clinical studies into TBI.

Key Points

  • Breakdown of the blood–brain barrier (BBB) follows traumatic brain injury (TBI) and can last from several days to years after the acute event

  • Secondary BBB breakdown—initiated within hours or days of injury—is associated with processes such as edema, neuroinflammation and cell death, and is considered to be potentially treatable

  • Experimental data indicate that BBB breakdown contributes to the clinical outcome of long-term TBI complications, such as Alzheimer disease, cognitive and psychological impairments, and epilepsy

  • A pressing need exists for new, practical and efficient diagnostic tools for the rapid detection and monitoring of BBB status

  • No accepted therapeutic protocols are available for the prevention or treatment of secondary damage resulting from BBB breakdown, although emergent treatment strategies aimed at modifying BBB-mediated injury are showing promise

  • Further basic and clinical research directed at the pathophysiology of BBB breakdown following TBI might provide novel targets for clinical intervention

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Figure 1: Pathophysiological events in traumatic brain injury.

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Acknowledgements

This work was supported by the Sonderforschungsbereich TR3, the Israel Science Foundation (grant 566/07, AF), the Binational US–Israel Science Foundation (grant BSF 2007,185) and the National Institute for Neurological Disorders and Stroke (grant 1RO1N5066005). The authors thank Ms Inez Mureinik (Research Authority, Ben-Gurion University of the Negev, Israel) for her useful comments and Dr Amihai Pima (Department of Urology, Rabin Medical Center, Israel) for assistance with Figure 1. Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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Shlosberg, D., Benifla, M., Kaufer, D. et al. Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6, 393–403 (2010). https://doi.org/10.1038/nrneurol.2010.74

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