Juvenile traumatic brain injury (jTBI) is the leading cause of death and disability in young children and adolescents. Despite its lasting detrimental effects on the developing brain, no pharmacological treatment exists. One of the pathological hallmarks of jTBI is edema. Astrocytes play a key role in the edema process, and have been hypothesized that numerous astrocyte networks allow communication and propagation of edema and secondary injury spread. Two key astrocyte proteins are hypothesized to have a central role in the edema process: Aquaporin 4 (AQP4) and Connexin 43 (Cx43). AQP4 is expressed extensively in astrocyte endfeet, which surrounds the blood vessels as part of the blood brain barrier (BBB). Cx43 is central in astrocyte to astrocyte connection and communication. We hypothesized that AQP4 acted as one of the potential passageway of water into the astrocyte, whereas Cx43 acted as the bridge between astrocytes once inside the brain. By blocking these strategically located pathways, we hypothesized that edema would decrease post-jTBI. In order to achieve specific inhibitions of APQ4 or Cx43, we utilized small interference RNA (siRNA), which is also an endogenous mechanism. We observed that after jTBI both AQP4 and Cx43 was significantly upregulated, edema was prominent, and reactive astrogliosis occurred. When siAQP4 was administered after jTBI, there was functional improvement, decreased edema, and decreased reactive astrogliosis. When siCx43 was administered, there was functional improvement and decreased reactive astrogliosis, but the level of edema did not change. From these findings, it can be seen that (1) AQP4 and Cx43 are upregulated acutely after jTBI, (2) both siAQP4 and siCx43 have therapeutic potentials after jTBI leading to functional recovery, (3) although both target astrocyte endfeet proteins, the mechanism of action seem to be different and AQP4 may play a more direct role in the edema process than Cx43. Future studies could focus on (1) a more clinically relevant delivery of siRNA for jTBI, (2) elucidating the mechanism behind functional improvement of siCx43, and (3) the relationship between AQP4 and Cx43 regarding astrocyte pathology after jTBI.
School of Medicine
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Brain Injuries - Physiopathology; Brain Edema - Physiopathology; Astrocytes - Metabolism; Aquaporins - Metabolism; Glial Fibrillary Acidic Protein
Subject - Local
Juvenile Traumatic Brain Injury; jTBI; Edema; Connexin 43; Reactive Astrogliosis
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Fukuda, Andrew Minoru, "Role of Astrocyte Network in Edema after Juvenile Traumatic Brain Injury" (2014). Loma Linda University Electronic Theses, Dissertations & Projects. 212.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives