Dataset Information

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

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.

SUBMITTER: Hagos FT

PROVIDER: S-EPMC6544476 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Hagos Fanuel T FT Adams Solomon M SM Poloyac Samuel M SM Kochanek Patrick M PM Horvat Christopher M CM Clark Robert S B RSB Empey Philip E PE

Experimental neurology 20190221

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 ...[more]

PMID: 30797827

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Project description:ImportanceAmong children, infants and toddlers have some of the highest rates of traumatic brain injury (TBI), but longitudinal information on their developmental outcomes to guide postinjury surveillance is sparse.ObjectiveTo evaluate infants' and toddlers' development over 3 years following TBI compared with those with orthopedic injury (OI).Design, setting, and participantsA longitudinal observational cohort study was conducted at 2 level 1 pediatric trauma centers from January 20, 2013, to September 30, 2015; data analysis was performed from May 12 to October 20, 2021. Participants included children injured when younger than 31 months with TBI or OI who received emergency department care.ExposuresMild, moderate, or severe TBI or OI.Main outcomes and measuresParents completed baseline measures representing preinjury status and 3-, 12-, 24-, and 36-month postinjury status, using the Ages & Stages Questionnaire-3 (ASQ-3), with a mean reference value of 50 and higher scores indicating more advanced development. Linear mixed models characterized children's outcomes for each ASQ-3 domain after adjustment for baseline ASQ-3, injury severity and group, age, injury mechanism (abuse or not), sex, prematurity, family function, social capital, and time. Interactions with time were evaluated.ResultsConsent for participation was provided for 195 children; 184 parents (94%) completed a baseline survey. The cohort included 168 children who completed at least 1 follow-up survey: 48 (29%) mild; 54 (32%) complicated mild/moderate; 21 (13%) severe TBI; and 45 (27%) orthopedic injury. The cohort included 95 boys (57%), 49% injured before age 1 year; and 13% injured by abuse. Mean (SD) age at the time of injury was 13.9 (9.4) months. At 36 months, children with mild or complicated mild/moderate TBI performed similarly to children with OI across ASQ-3 domains. Children with severe TBI performed poorly as shown by negative mean differences in communication (-8.8; 95% CI, -13.8 to -3.8); gross motor (-10.1; 95% CI, -15.1 to -5.1); problem solving (-6.6; 95% CI, -11.2 to -1.9), and personal social (-6.3; 95% CI, -10.4 to -2.1) domains with little recovery over time. Children with abusive injury experienced decrements in ability over time in fine motor and personal social skills. Social capital was protective in communication (mean, 1.5; 95% CI, 0.3-2.7) and problem solving (mean, 1.2; 95% CI, 0.1-2.3) domains.Conclusions and relevanceIn this cohort study of children with TBI, children with severe injury showed little recovery. These findings suggest that early childhood intervention is needed, while children with milder injury remained on their developmental track and should continue routine developmental surveillance.

Project description:The rat high-impact free weight drop model mimics the diffuse axonal injury caused by severe traumatic brain injury in humans, while severe controlled cortical impact can produce a severe traumatic brain injury model using precise strike parameters. In this study, we compare the pathological mechanisms and pathological changes between two rat severe brain injury models to identify the similarities and differences. The severe controlled cortical impact model was produced by an electronic controlled cortical impact device, while the severe free weight drop model was produced by dropping a 500 g free weight from a height of 1.8 m through a plastic tube. Body temperature and mortality were recorded, and neurological deficits were assessed with the modified neurological severity score. Brain edema and blood-brain barrier damage were evaluated by assessing brain water content and Evans blue extravasation. In addition, a cytokine array kit was used to detect inflammatory cytokines. Neuronal apoptosis in the brain and brainstem was quantified by immunofluorescence staining. Both the severe controlled cortical impact and severe free weight drop models exhibited significant neurological impairments and body temperature fluctuations. More severe motor dysfunction was observed in the severe controlled cortical impact model, while more severe cognitive dysfunction was observed in the severe free weight drop model. Brain edema, inflammatory cytokine changes and cortical neuronal apoptosis were more substantial and blood-brain barrier damage was more focal in the severe controlled cortical impact group compared with the severe free weight drop group. The severe free weight drop model presented with more significant apoptosis in the brainstem and diffused blood-brain barrier damage, with higher mortality and lower repeatability compared with the severe controlled cortical impact group. Severe brainstem damage was not found in the severe controlled cortical impact model. These results indicate that the severe controlled cortical impact model is relatively more stable, more reproducible, and shows obvious cerebral pathological changes at an earlier stage. Therefore, the severe controlled cortical impact model is likely more suitable for studies on severe focal traumatic brain injury, while the severe free weight drop model may be more apt for studies on diffuse axonal injury. All experimental procedures were approved by the Ethics Committee of Animal Experiments of Tianjin Medical University, China (approval No. IRB2012-028-02) in February 2012.

Dataset Information

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

Publications

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

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