Glycerol accumulation in edema formation following diffuse traumatic brain injury

Neurol Res. 2012 Jun;34(5):462-8. doi: 10.1179/1743132812Y.0000000014. Epub 2012 Mar 20.

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.

MeSH terms

  • 2-Methoxyestradiol
  • Animals
  • Aquaporins / metabolism
  • Brain Edema / etiology*
  • Brain Edema / metabolism*
  • Brain Edema / prevention & control
  • Brain Injuries / complications*
  • Brain Injuries / drug therapy
  • Disease Models, Animal
  • Estradiol / administration & dosage
  • Estradiol / analogs & derivatives
  • Gene Expression Regulation / drug effects
  • Glycerol / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Tubulin Modulators / administration & dosage

Substances

  • Aqp9 protein, rat
  • Aquaporins
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Tubulin Modulators
  • Estradiol
  • 2-Methoxyestradiol
  • Glycerol