title: Glycerol accumulation in edema formation following diffuse traumatic brain injury.
abstract: Traumatic brain injury (TBI) induces brain edema via water and glycerol transport channels, called aquaporins (AQPs). The passage of glycerol across brain cellular compartments has been shown during edema. Using a modified impact/head acceleration rodent model of diffuse TBI, we assessed the role of hypoxia inducible factor (HIF)-1alpha in regulating AQP9 expression and glycerol accumulation during the edema formation. Adult (400-425 g) male Sprague-Dawley rats received a closed head injury with a weight drop (450 g, 2-m height) and were allowed to survive up to 48 hours. Some rat groups were administered 2-methoxyestradiol (2ME2, a HIF-1alpha inhibitor) 30 minutes after injury and were euthanized at 4 and 24 hours after injury. Brain edema was measured directly by water content, and glycerol concentration was determined by the Cayman Glycerol Assay. HIF-1alpha and AQP9 protein levels were assessed by Western immunoblotting. This study demonstrated a significant (P<0·05) increase in brain water content at 4-48 hours following impact. Cerebral glycerol was significantly (P<0.05) up-regulated at as early as 1 hour and remained at high levels for up to 48 hours. Similarly, significant (P<0.05) increases in HIF-1alpha and AQP9 protein levels were found at 1 hour and up to 48 hours after injury. Compared to untreated but injured rats, inhibition of HIF-1alpha by 2ME2 significantly (P<0.05) reduced the TBI-induced AQP9 up-regulation. This reduction was temporally associated with significant (P<0.05) decreases in both edema and glycerol accumulation. The data suggested an associated induction of HIF-1alpha, AQP9, and extracellular glycerol accumulation in edema formation following diffuse TBI. The implication of HIF-1alpha and AQP9 underlying TBI-induced edema formation offers possibilities for novel TBI therapies.
authors.affiliation: Wayne State University, School of Medicine, Detroit, MI 48201, USA.
authors.forename: Ahmer
authors.initials: A
authors.lastname: Ali
authors.forename: Sanjay
authors.initials: S
authors.lastname: Konakondla
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Zwagerman
authors.forename: Changya
authors.initials: C
authors.lastname: Peng
authors.forename: Steven
authors.initials: S
authors.lastname: Schafer
authors.forename: Jamie Y
authors.initials: JY
authors.lastname: Ding
authors.forename: David
authors.initials: D
authors.lastname: Dornbos
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Sikharam
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Geng
authors.forename: Murali
authors.initials: M
authors.lastname: Guthikonda
authors.forename: Christian W
authors.initials: CW
authors.lastname: Kreipke
authors.forename: José A
authors.initials: JA
authors.lastname: Rafols
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D020346:Aquaporins / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005786:Gene Expression Regulation / Q000187:drug effects; D005990:Glycerol / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D050257:Tubulin Modulators / Q000008:administration & dosage
chemical_list: C491637:Aqp9 protein, rat; D020346:Aquaporins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D005990:Glycerol