Acetazolamide Mitigates Astrocyte Cellular Edema Following Mild Traumatic Brain Injury.
Non-penetrating or mild traumatic brain injury (mTBI) is commonly experienced in accidents, the battlefield and in full-contact sports. Astrocyte cellular edema is one of the major factors that leads to high morbidity post-mTBI. Various studies have reported an upregulation of aquaporin-4 (AQP4), a water channel protein, following brain injury. AZA is an antiepileptic drug that has been shown to inhibit AQP4 expression and in this study we investigate the drug as a therapeutic to mitigate the extent of mTBI induced cellular edema. We hypothesized that mTBI-mediated astrocyte dysfunction, initiated by increased intracellular volume, could be reduced when treated with AZA. We tested our hypothesis in a three-dimensional in vitro astrocyte model of mTBI. Samples were subject to no stretch (control) or one high-speed stretch (mTBI) injury. AQP4 expression was significantly increased 24 hours after mTBI. mTBI resulted in a significant increase in the cell swelling within 30 min of mTBI, which was significantly reduced in the presence of AZA. Cell death and expression of S100B was significantly reduced when AZA was added shortly before mTBI stretch. Overall, our data point to occurrence of astrocyte swelling immediately following mTBI, and AZA as a promising treatment to mitigate downstream cellular mortality.
Department of Biomedical Engineering, University of Arkansas, Fayetteville AR 72701, USA.
Nasya M
NM
Sturdivant
Department of Biomedical Engineering, University of Arkansas, Fayetteville AR 72701, USA.
Sean G
SG
Smith
Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson AR 72079, USA.
Syed F
SF
Ali
Department of Biomedical Engineering, University of Arkansas, Fayetteville AR 72701, USA.
Jeffrey C
JC
Wolchok
Department of Biomedical Engineering, University of Arkansas, Fayetteville AR 72701, USA.
Kartik
K
Balachandran
D000086:Acetazolamide / Q000008:administration & dosage*; D051401:Aquaporin 4 / Q000235:genetics*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004487:Edema / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008855:Microscopy, Electron, Scanning; D014867:Water / Q000737:chemistry
C496030:AQP4 protein, human; D051401:Aquaporin 4; D014867:Water; D000086:Acetazolamide