Early to Long-Term Alterations of CNS Barriers After Traumatic Brain Injury: Considerations for Drug Development.
AAPS J. 2017-09-13; 19(6): 1615-1625
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1. AAPS J. 2017 Nov;19(6):1615-1625. doi: 10.1208/s12248-017-0123-3. Epub 2017 Sep
Early to Long-Term Alterations of CNS Barriers After Traumatic Brain Injury:
Considerations for Drug Development.
Rodriguez-Grande B(1), Ichkova A(1), Lemarchant S(1), Badaut J(2)(3).
(1)CNRS UMR5287, University of Bordeaux, 146 rue Léo Saignat, 33076, Bordeaux
(2)CNRS UMR5287, University of Bordeaux, 146 rue Léo Saignat, 33076, Bordeaux
Cedex, France. .
(3)Basic Science Departments, Loma Linda University School of Medicine, Loma
Linda, California, USA. .
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.
PMID: 28905273 [Indexed for MEDLINE]