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Early to Long-Term Alterations of CNS Barriers After Traumatic Brain Injury: Considerations for Drug Development

  • Review Article
  • Theme: CNS Barriers in Health and Disease
  • Published:
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Abstract

Traumatic brain injury (TBI) is one of the leading causes of death and disability, particularly amongst the young and the elderly. The functions of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are strongly impaired after TBI, thus affecting brain homeostasis. Following the primary mechanical injury that characterizes TBI, a secondary injury develops over time, including events such as edema formation, oxidative stress, neuroinflammation, and alterations in paracelullar and transcellular transport. To date, most therapeutic interventions for TBI have aimed at direct neuroprotection during the acute phase and have not been successful. Targeting the barriers of the central nervous system (CNS) could be a wider therapeutic approach, given that restoration of brain homeostasis would benefit all brain cells, including neurons. Importantly, BBB disregulation has been observed even years after TBI, concomitantly with neurological and psychosocial sequelae; however, treatments targeting the post-acute phase are scarce. Here, we review the mechanisms of primary and secondary injury of CNS barriers, the accumulating evidence showing long-term damage to these structures and some of the therapies that have targeted these mechanisms. Finally, we discuss how the injury characteristics (hemorrhagic vs non-hemorrhagic, involvement of head rotation, gray vs white matter), the sex, and the age of the patient need to be carefully considered to improve clinical trial design and outcome interpretation, and to improve future drug development.

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Acknowledgements

This work was supported by grants from Eranet neuron CNS-aflame consortium (JB) and TRAINS (JB) and TRAIL-Labex ANR Vasc-TBI (JB).

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Authors and Affiliations

  1. CNRS UMR5287, University of Bordeaux, 146 rue Léo Saignat, 33076, Bordeaux Cedex, France

    Beatriz Rodriguez-Grande, Aleksandra Ichkova, Sighild Lemarchant & Jerome Badaut

  2. Basic Science Departments, Loma Linda University School of Medicine, Loma Linda, California, USA

    Jerome Badaut

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  1. Beatriz Rodriguez-Grande
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  2. Aleksandra Ichkova
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  4. Jerome Badaut
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Correspondence to Jerome Badaut.

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Rodriguez-Grande, B., Ichkova, A., Lemarchant, S. et al. Early to Long-Term Alterations of CNS Barriers After Traumatic Brain Injury: Considerations for Drug Development. AAPS J 19, 1615–1625 (2017). https://doi.org/10.1208/s12248-017-0123-3

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