Disruption of blood-brain barrier (BBB) is a key secondary event that exacerbates brain damage following traumatic brain injury (TBI). BBB disruption is particularly damaging to the developing brain – which is highly vulnerable to various stress stimuli, resulting in increased brain swelling, disrupted cerebral blood flow (CBF) autoregulation, long-term disabilities and death following TBI in young demographic. Unsurprisingly, BBB disruption and the resultant cerebral edema have emerged as therapeutic targets in juvenile TBI. It is therefore important to understand the molecular players and mechanisms involved in TBI-induced BBB disruption in the juvenile brain. To this end, the endothelial caveolins and c-Jun N-terminal kinases (JNKs) were identified as proteins of interest in the regulation of brain endothelial permeability after injury. These were investigated under a three-fold aim. The first was to characterize the acute and long-term histological and functional changes occurring following injury to the developing brain. Second was the attempt to profile the changes in expression patterns of caveolins after juvenile TBI in conjunction with BBB disruption. And lastly, the effects of molecular agents that target JNK (DJNKI-1) and caveolin (cavtratin) pathways respectively were examined on BBB integrity, and on imaging, histological and functional outcomes. To achieve these aims, an experimental model of TBI in juvenile rats was developed and characterized. Evidence emerged that long-term white matter dysfunction occurs in this model, in parallel with delayed neurodevelopment and persistence of behavioral deficits, which mimics data from clinical and longitudinal TBI observations. There was both acute and long-term increase in the expression level of caveolin-1 in the endothelium and reactive astrocytes following juvenile TBI. Furthermore, acute administration of cavtratin, a peptide mimetic of caveolin-1 scaffolding domain, markedly reduced edema formation and lesion volume without improving sensorimotor outcome in the acute time points. However, competitive inhibition of the JNK pathway with acute administration of DJNKI-1 markedly ameliorates BBB permeability, reduced edema formation, and improves neuroimaging and neurological outcomes at both acute and chronic time points. These findings could potentially be exploited for future therapeutic applications in juvenile brain trauma.
School of Medicine
Pearce, William J.
Zhang, John H.
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Brain Injuries - Physiopathology; Brain Edema; Brain - Growth & Development; Endothelium - Vascular; Vascular Endothelial Growth Factors; Vesicular Transport Proteins; Caveolins; JNK Mitogen-Activated Protein Kinases; Blood-Brain Barrier
Subject - Local
Cerebral Brain Flow; Juvenile Brains; Brain Endothelial Permeability; Traumatic Brain Injury; TBI; BBB;
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This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.
Ajao, David Olufemi, "Caveolins and NJKs Influence Brain Endothelial Permeability after Juvenile TBI" (2013). Loma Linda University Electronic Theses, Dissertations & Projects. Paper 217.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives