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Exp Neurol. 2019 Jul;317:10-21. doi: 10.1016/j.expneurol.2019.02.011. Epub 2019 Feb 21.

Membrane transporters in traumatic brain injury: Pathological, pharmacotherapeutic, and developmental implications.

Author information

1
Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, PA, United States of America.
2
Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, PA, United States of America; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States of America.
3
Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States of America; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America; UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States of America.
4
Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States of America; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America; UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States of America. Electronic address: clarkrs@ccm.upmc.edu.
5
Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, PA, United States of America; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States of America. Electronic address: pempey@pitt.edu.

Abstract

Membrane transporters regulate the trafficking of endogenous and exogenous molecules across biological barriers and within the neurovascular unit. In traumatic brain injury (TBI), they moderate the dynamic movement of therapeutic drugs and injury mediators among neurons, endothelial cells and glial cells, thereby becoming important determinants of pathogenesis and effective pharmacotherapy after TBI. There are three ways transporters may impact outcomes in TBI. First, transporters likely play a key role in the clearance of injury mediators. Second, genetic association studies suggest transporters may be important in the transition of TBI from acute brain injury to a chronic neurological disease. Third, transporters dynamically control the brain penetration and efflux of many drugs and their distribution within and elimination from the brain, contributing to pharmacoresistance and possibly in some cases pharmacosensitivity. Understanding the nature of drugs or candidate drugs in development with respect to whether they are a transporter substrate or inhibitor is relevant to understand whether they distribute to their target in sufficient concentrations. Emerging data provide evidence of altered expression and function of transporters in humans after TBI. Genetic variability in expression and/or function of key transporters adds an additional dynamic, as shown in recent clinical studies. In this review, evidence supporting the role of individual membrane transporters in TBI are discussed as well as novel strategies for their modulation as possible therapeutic targets. Since data specifically targeting pediatric TBI are sparse, this review relies mainly on experimental studies using adult animals and clinical studies in adult patients.

KEYWORDS:

ATP-binding cassette transporters; Blood-brain barrier; Multidrug resistance; Neurovascular unit; Solute carriers; Traumatic brain injury

PMID:
30797827
PMCID:
PMC6544476
[Available on 2020-07-01]
DOI:
10.1016/j.expneurol.2019.02.011

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